Pyrazole compounds as modulators of FSHR and uses thereof

ABSTRACT

The present invention relates to pyrazole compounds, and pharmaceutically acceptable compositions thereof, useful as positive allosteric modulators of follicle stimulating hormone receptor (FSHR).

RELATED APPLICATIONS

This application is a U.S. national stage application of PCTinternational application PCT/US14/43838, filed on Jun. 24, 2014, whichclaims the benefit of U.S. provisional application 61/838,460, filed onJun. 24, 2013, and U.S. provisional application 61/898,608, filed onNov. 1, 2013. The contents of the aforementioned applications are herebyincorporated by reference in their entireties.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to pyrazole compounds useful as agonistsof follicle stimulating hormone receptor (FSHR). The invention alsoprovides pharmaceutically acceptable compositions comprising compoundsof the present invention and methods of using said compositions in thetreatment of various disorders.

BACKGROUND OF THE INVENTION

Gonadotropins serve important functions in a variety of bodily functionsincluding metabolism, temperature regulation and the reproductiveprocess. Gonadotropins act on specific gonadal cell types to initiateovarian and testicular differentiation and steroidogenesis. Thegonadotropin FSH (follicle stimulating hormone) is released from theanterior pituitary under the influence of gonadotropin-releasing hormoneand estrogens, and from the placenta during pregnancy. FSH is aheterodimeric glycoprotein hormone that shares structural similaritieswith luteinizing hormone (LH) and thyroid stimulating hormone (TSH),both of which are also produced in the pituitary gland, and chorionicgonadotropin (CG), which is produced in the placenta. In the female, FSHplays a pivotal role in the stimulation of follicle development andmaturation and in addition, it is the major hormone regulating secretionof estrogens, whereas LH induces ovulation. In the male, FSH isresponsible for the integrity of the seminiferous tubules and acts onSertoli cells to support gametogenesis.

The hormones are relatively large (28-38 kDa) and are composed of acommon α-subunit non-covalently bound to a distinct β-subunit thatconfers receptor binding specificity. The cellular receptor for thesehormones is expressed on testicular Sertoli cells and ovarian granulosacells. The FSH receptor is known to be members of the G protein-coupledclass of membrane-bound receptors, which when activated stimulate anincrease in the activity of adenylyl cyclase. This results in anincrease in the level of the intracellular second messenger adenosine3′,5′-monophosphate (cAMP), which in turn causes increased steroidsynthesis and secretion. Hydropathicity plots of the amino acidsequences of these receptors reveal three general domains: a hydrophilicamino-terminal region, considered to be the amino-terminal extracellulardomain; seven hydrophobic segments of membrane-spanning length,considered to be the transmembrane domain; and a carboxy-terminal regionthat contains potential phosphorylation sites (serine, threonine, andtyrosine residues), considered to be the carboxy-terminal intracellularor cytoplasmic domain. The glycoprotein hormone receptor family isdistinguished from other G protein-coupled receptors, such as theβ-2-adrenergic, rhodopsin, and substance K receptors, by the large sizeof the hydrophilic amino-terminal domain, which is involved in hormonebinding.

Annually in the U.S. there are 2.4 million couples experiencinginfertility that are potential candidates for treatment. FSH, eitherextracted from urine or produced by recombinant DNA technology, is aparenterally-administered protein product used by specialists forovulation induction and for controlled ovarial hyperstimulation. Whereasovulation induction is directed at achieving a single follicle toovulate, controlled ovarial hyperstimulation is directed at harvestingmultiple oocytes for use in various in-vitro assisted reproductivetechnologies, e.g. in-vitro fertilization (IVF). FSH is also usedclinically to treat male hypogonadism and male infertility, e.g. sometypes of failure of spermatogenesis.

FSHR is a highly specific target in the ovarian follicle growth processand is exclusively expressed in the ovary. However, the use of FSH islimited by its high cost, lack of oral dosing, and need of extensivemonitoring by specialist physicians. Hence, identification of anon-peptidic small molecule substitute for FSH that could potentially bedeveloped for oral administration is desirable. Low molecular weight FSHmimetics with agonistic properties are disclosed in the internationalapplications WO 2002/09706 and WO 2010/136438 as well as the U.S. Pat.No. 6,653,338. There is still a need for low molecular weight hormonemimetics that selectively activate FSHR.

SUMMARY OF THE INVENTION

It has now been found that compounds of this invention, andpharmaceutically acceptable compositions thereof, are effective asmodulators of FSHR. Such compounds have general formula I:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A,X, Y, Z, R¹, R², R³, R⁴, R⁵, R⁶, n, and p, is as defined and describedin embodiments herein.

Compounds of the present invention, and pharmaceutically acceptablecompositions thereof, are useful for treating a variety of diseases,disorders or conditions, associated with abnormal cellular responsestriggered by follicle stimulating hormone events. Such diseases,disorders, or conditions include those described herein.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 1. General Description ofCompounds of the Invention

In certain embodiments, the present invention provides modulators offollicle stimulating hormone receptor (FSHR). In certain embodiments,the present invention provides positive allosteric modulators of FSHR.In some embodiments, such compounds include those of the formulaedescribed herein, or a pharmaceutically acceptable salt thereof, whereineach variable is as defined and described herein.

2. Compounds and Definitions

Compounds of this invention include those described generally above, andare further illustrated by the classes, subclasses, and speciesdisclosed herein. As used herein, the following definitions shall applyunless otherwise indicated. For purposes of this invention, the chemicalelements are identified in accordance with the Periodic Table of theElements, CAS version, Handbook of Chemistry and Physics, 75^(th) Ed.Additionally, general principles of organic chemistry are described in“Organic Chemistry”, Thomas Sorrell, University Science Books,Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th) Ed.,Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, theentire contents of which are hereby incorporated by reference.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation, or a monocyclic hydrocarbonor bicyclic hydrocarbon that is completely saturated or that containsone or more units of unsaturation, but which is not aromatic (alsoreferred to herein as “carbocycle” “cycloaliphatic” or “cycloalkyl”),that has a single point of attachment to the rest of the molecule.Unless otherwise specified, aliphatic groups contain 1-6 aliphaticcarbon atoms. In some embodiments, aliphatic groups contain 1-5aliphatic carbon atoms. In other embodiments, aliphatic groups contain1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groupscontain 1-3 aliphatic carbon atoms, and in yet other embodiments,aliphatic groups contain 1-2 aliphatic carbon atoms. In someembodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refersto a monocyclic C₃-C₆ hydrocarbon that is completely saturated or thatcontains one or more units of unsaturation, but which is not aromatic,that has a single point of attachment to the rest of the molecule.Exemplary aliphatic groups are linear or branched, substituted orunsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl groups andhybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or(cycloalkyl)alkenyl.

The term “lower alkyl” refers to a C₁₋₄ straight or branched alkylgroup. Exemplary lower alkyl groups are methyl, ethyl, propyl,isopropyl, butyl, isobutyl, and tert-butyl.

The term “lower haloalkyl” refers to a C₁₋₄ straight or branched alkylgroup that is substituted with one or more halogen atoms.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, orphosphorus (including, any oxidized form of nitrogen, sulfur, orphosphorus; the quaternized form of any basic nitrogen or; asubstitutable nitrogen of a heterocyclic ring, for example N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as inN-substituted pyrrolidinyl)).

The term “unsaturated”, as used herein, means that a moiety has one ormore units of unsaturation.

As used herein, the term “bivalent C₁₋₈ (or C₁₋₆) saturated orunsaturated, straight or branched, hydrocarbon chain”, refers tobivalent alkylene, alkenylene, and alkynylene chains that are straightor branched as defined herein.

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(n)—, wherein n is apositive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylenegroup in which one or more methylene hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “alkenylene” refers to a bivalent alkenyl group. A substitutedalkenylene chain is a polymethylene group containing at least one doublebond in which one or more hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “halogen” means F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic andbicyclic ring systems having a total of five to fourteen ring members,wherein at least one ring in the system is aromatic and wherein eachring in the system contains three to seven ring members. The term “aryl”is used interchangeably with the term “aryl ring”. In certainembodiments of the present invention, “aryl” refers to an aromatic ringsystem. Exemplary aryl groups are phenyl, biphenyl, naphthyl, anthracyland the like, which optionally includes one or more substituents. Alsoincluded within the scope of the term “aryl”, as it is used herein, is agroup in which an aromatic ring is fused to one or more non-aromaticrings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, ortetrahydronaphthyl, and the like.

The terms “heteroaryl” and “heteroar-”, used alone or as part of alarger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer togroups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms;having 6, 10, or 14 π electrons shared in a cyclic array; and having, inaddition to carbon atoms, from one to five heteroatoms. The term“heteroatom” refers to nitrogen, oxygen, or sulfur, and includes anyoxidized form of nitrogen or sulfur, and any quaternized form of a basicnitrogen. Heteroaryl groups include, without limitation, thienyl,furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl,purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and“heteroar-”, as used herein, also include groups in which aheteroaromatic ring is fused to one or more aryl, cycloaliphatic, orheterocyclyl rings, where the radical or point of attachment is on theheteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl,benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl,benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Aheteroaryl group is optionally mono- or bicyclic. The term “heteroaryl”is used interchangeably with the terms “heteroaryl ring”, “heteroarylgroup”, or “heteroaromatic”, any of which terms include rings that areoptionally substituted. The term “heteroaralkyl” refers to an alkylgroup substituted by a heteroaryl, wherein the alkyl and heteroarylportions independently are optionally substituted.

As used herein, the terms “heterocycle”, “heterocyclyl”, “heterocyclicradical”, and “heterocyclic ring” are used interchangeably and refer toa stable 5- to 7-membered monocyclic or 7-10-membered bicyclicheterocyclic moiety that is either saturated or partially unsaturated,and having, in addition to carbon atoms, one or more, preferably one tofour, heteroatoms, as defined above. When used in reference to a ringatom of a heterocycle, the term “nitrogen” includes a substitutednitrogen. As an example, in a saturated or partially unsaturated ringhaving 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, thenitrogen is N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl),or ⁺NR (as in N-substituted pyrrolidinyl).

A heterocyclic ring can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted. Examples of such saturatedor partially unsaturated heterocyclic radicals include, withoutlimitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl,piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. Theterms “heterocycle”, “heterocyclyl”, “heterocyclyl ring”, “heterocyclicgroup”, “heterocyclic moiety”, and “heterocyclic radical”, are usedinterchangeably herein, and also include groups in which a heterocyclylring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings,such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, ortetrahydroquinolinyl, where the radical or point of attachment is on theheterocyclyl ring. A heterocyclyl group is optionally mono- or bicyclic.The term “heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl, wherein the alkyl and heterocyclyl portions independentlyare optionally substituted.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond. The term “partiallyunsaturated” is intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aryl or heteroarylmoieties, as herein defined.

As described herein, certain compounds of the invention contain“optionally substituted” moieties. In general, the term “substituted”,whether preceded by the term “optionally” or not, means that one or morehydrogens of the designated moiety are replaced with a suitablesubstituent. “Substituted” applies to one or more hydrogens that areeither explicit or implicit from the structure (e.g.,

refers to at least

refers to at least

Unless otherwise indicated, an “optionally substituted” group has asuitable substituent at each substitutable position of the group, andwhen more than one position in any given structure is substituted withmore than one substituent selected from a specified group, thesubstituent is either the same or different at every position.Combinations of substituents envisioned by this invention are preferablythose that result in the formation of stable or chemically feasiblecompounds. The term “stable”, as used herein, refers to compounds thatare not substantially altered when subjected to conditions to allow fortheir production, detection, and, in certain embodiments, theirrecovery, purification, and use for one or more of the purposesdisclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently deuterium; halogen;—(CH₂)₀₋₄R^(∘); —(CH₂)₀₋₄OR^(∘); —O(CH₂)₀₋₄R^(∘), —O—(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄CH(OR^(∘))₂; —(CH₂)₀₋₄SR^(∘); —(CH₂)₀₋₄Ph, which are optionallysubstituted with R^(∘); —(CH₂)₀₋₄O(CH₂)₀₋₄Ph which is optionallysubstituted with R^(∘); —CH═CHPh, which is optionally substituted withR^(∘); —(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which is optionally substituted withR^(∘); —NO₂; —CN; —N₃; —(CH₂)₀₋₄N(R^(∘))₂; —(CH₂)₀₋₄N(R^(∘))C(O)R^(∘);—N(R^(∘))C(S)R^(∘); —(CH₂)₀₋₄N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))C(S)NR^(∘)₂; —(CH₂)₀₋₄N(R^(∘))C(O)OR^(∘); —N(R^(∘))N(R^(∘))C(O)R^(∘);—N(R^(∘))N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))N(R^(∘))C(O)OR^(∘);—(CH₂)₀₋₄C(O)R^(∘); —C(S)R^(∘); —(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄C(O)SR^(∘); —(CH₂)₀₋₄C(O)OSiR^(∘) ₃; —(CH₂)₀₋₄C(O)R^(∘);—OC(O)(CH₂)₀₋₄SR^(∘), SC(S)SR^(∘); —(CH₂)₀₋₄SC(O)R^(∘);—(CH₂)₀₋₄C(O)NR^(∘) ₂; —C(S)NR^(∘) ₂; —C(S)SR^(∘); —SC(S)SR^(∘),—(CH₂)₀₋₄OC(O)NR^(∘) ₂; —C(O)N(OR^(∘))R^(∘); —C(O)C(O)R^(∘);—C(O)CH₂C(O)R^(∘); —C(NOR^(∘))R^(∘); —(CH₂)₀₋₄SSR^(∘);—(CH₂)₀₋₄S(O)₂R^(∘); —(CH₂)₀₋₄S(O)₂OR^(∘); —(CH₂)₀₋₄OS(O)₂R^(∘);—S(O)₂NR^(∘) ₂; —(CH₂)₀₋₄S(O)R^(∘); —N(R^(∘))S(O)₂NR^(∘) ₂;—N(R^(∘))S(O)₂R^(∘); —N(OR^(∘))R^(∘); —C(NH)NR^(∘) ₂; —P(O)₂R^(∘);—P(O)R^(∘) ₂; —OP(O)R^(∘) ₂; —OP(O)(OR^(∘))₂; SiR^(∘) ₃; —(C₁₋₄ straightor branched alkylene)O—N(R^(∘))₂; or —(C₁₋₄ straight or branchedalkylene)C(O)O—N(R^(∘))₂, wherein each R^(∘) is optionally substitutedas defined below and is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(∘), taken together with their intervening atom(s), form a3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, which is optionally substituted as definedbelow.

Suitable monovalent substituents on R^(∘) (or the ring formed by takingtwo independent occurrences of R^(∘) together with their interveningatoms), are independently deuterium, halogen, —(CH₂)₀₋₂R^(●),-(haloR^(●)), —(CH₂)O₂OH, —(CH₂)₀₋₂OR^(●), —(CH₂)O₂CH(OR^(●))₂;—O(haloR^(●)), —CN, —N₃, —(CH₂)₀₋₂C(O)R^(●), —(CH₂)₀₋₂C(O)OH,—(CH₂)₀₋₂C(O)OR^(●), —(CH₂)₀₋₂SR^(●), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂,—(CH₂)₀₋₂NHR^(●), —(CH₂)₀₋₂NR^(●) ₂, —NO₂, —SiR^(●) ₃, —OSiR^(●) ₃,—C(O)SR^(●), —(C₁₋₄ straight or branched alkylene)C(O)OR^(●), or—SSR^(●) wherein each R^(●) is unsubstituted or where preceded by “halo”is substituted only with one or more halogens, and is independentlyselected from C₁₋₄ aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. Suitabledivalent substituents on a saturated carbon atom of R^(∘) include ═O and═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))₂₋₃O—, or—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic which is substituted as defined below, oran unsubstituted 5-6-membered saturated, partially unsaturated, or arylring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR*₂)₂₋₃O—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic which is optionally substitutedas defined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen,—R^(●), -(haloR^(●)), —OH, —OR*, —O(haloR^(●)), —CN, —C(O)OH,—C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein each R^(●) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which is optionallysubstituted as defined below, unsubstituted —OPh, or an unsubstituted5-6-membered saturated, partially unsaturated, or aryl ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(†), taken together with their intervening atom(s) form anunsubstituted 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(†) are independentlyhalogen, —R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN,—C(O)OH, —C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein eachR^(●) is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

In certain embodiments, the terms “optionally substituted”, “optionallysubstituted alkyl,” “optionally substituted “optionally substitutedalkenyl,” “optionally substituted alkynyl”, “optionally substitutedcarbocyclic,” “optionally substituted aryl”, “optionally substitutedheteroaryl,” “optionally substituted heterocyclic,” and any otheroptionally substituted group as used herein, refer to groups that aresubstituted or unsubstituted by independent replacement of one, two, orthree or more of the hydrogen atoms thereon with typical substituentsincluding, but not limited to:

—F, —Cl, —Br, —I, deuterium,

—OH, protected hydroxy, alkoxy, oxo, thiooxo,

—NO₂, —CN, CF₃, N₃,

—NH₂, protected amino, —NH alkyl, —NH alkenyl, —NH alkynyl, —NHcycloalkyl, —NH— aryl, —NH-heteroaryl, —NH-heterocyclic, -dialkylamino,-diarylamino, -diheteroarylamino,

—O— alkyl, —O— alkenyl, —O— alkynyl, —O— cycloalkyl, —O-aryl,—O-heteroaryl, —O-heterocyclic,

—C(O)— alkyl, —C(O)— alkenyl, —C(O)— alkynyl, —C(O)— carbocyclyl,—C(O)-aryl, —C(O)— heteroaryl, —C(O)-heterocyclyl,

—CONH₂, —CONH— alkyl, —CONH— alkenyl, —CONH— alkynyl, —CONH-carbocyclyl,—CONH-aryl, —CONH-heteroaryl, —CONH-heterocyclyl,

—OCO₂— alkyl, —OCO₂— alkenyl, —OCO₂— alkynyl, —OCO₂— carbocyclyl,—OCO₂-aryl, —OCO₂-heteroaryl, —OCO₂-heterocyclyl, —OCONH₂, —OCONH—alkyl, —OCONH— alkenyl, —OCONH— alkynyl, —OCONH— carbocyclyl, —OCONH—aryl, —OCONH— heteroaryl, —OCONH— heterocyclyl,

—NHC(O)— alkyl, —NHC(O)— alkenyl, —NHC(O)— alkynyl, —NHC(O)—carbocyclyl, —NHC(O)-aryl, —NHC(O)-heteroaryl, —NHC(O)-heterocyclyl,—NHCO₂— alkyl, —NHCO₂— alkenyl, —NHCO₂— alkynyl, —NHCO₂— carbocyclyl,—NHCO₂— aryl, —NHCO₂— heteroaryl, —NHCO₂-heterocyclyl, —NHC(O)NH₂,—NHC(O)NH— alkyl, —NHC(O)NH— alkenyl, —NHC(O)NH— alkenyl,—NHC(O)NH-carbocyclyl, —NHC(O)NH-aryl, —NHC(O)NH-heteroaryl, —NHC(O)NH—heterocyclyl, NHC(S)NH₂, —NHC(S)NH— alkyl, —NHC(S)NH— alkenyl,—NHC(S)NH— alkynyl, —NHC(S)NH— carbocyclyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocyclyl, —NHC(NH)NH₂, —NHC(NH)NH—alkyl, —NHC(NH)NH— -alkenyl, —NHC(NH)NH— alkenyl, —NHC(NH)NH—carbocyclyl, —NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)NH—heterocyclyl, —NHC(NH)— alkyl, —NHC(NH)— alkenyl, —NHC(NH)— alkenyl,—NHC(NH)— carbocyclyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocyclyl,

—C(NH)NH— alkyl, —C(NH)NH— alkenyl, —C(NH)NH— alkynyl, —C(NH)NH—carbocyclyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl, —C(NH)NH-heterocyclyl,

—S(O)— alkyl, —S(O)— alkenyl, —S(O)— alkynyl, —S(O)— carbocyclyl,—S(O)-aryl, —S(O)-heteroaryl, —S(O)-heterocyclyl —SO₂NH₂, —SO₂NH— alkyl,—SO₂NH— alkenyl, —SO₂NH— alkynyl, —SO₂NH— carbocyclyl, —SO₂NH— aryl,—SO₂NH— heteroaryl, —SO₂NH— heterocyclyl,

—NHSO₂— alkyl, —NHSO₂— alkenyl, —NHSO₂— alkynyl, —NHSO₂— carbocyclyl,—NHSO₂-aryl, —NHSO₂-heteroaryl, —NHSO₂-heterocyclyl,

—CH₂NH₂, —CH₂SO₂CH₃,

-mono-, di-, or tri-alkyl silyl,

-alkyl, -alkenyl, -alkynyl, -aryl, -arylalkyl, -heteroaryl,-heteroarylalkyl, heterocycloalkyl, -cycloalkyl, -carbocyclic,-heterocyclic, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy,-methoxyethoxy, —SH, —S— alkyl, —S— alkenyl, —S— alkynyl, —S—carbocyclyl, —S-aryl, —S-heteroaryl, —S-heterocyclyl, ormethylthiomethyl.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge etal., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from suitable inorganic and organicacids and bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid and perchloric acid or with organic acids such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid ormalonic acid or by using other methods used in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate,propionate, stearate, succinate, sulfate, tartrate, thiocyanate,p-toluenesulfonate, undecanoate, valerate salts, and the like.

Salts derived from appropriate bases include alkali metal, alkalineearth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. Representative alkali oralkaline earth metal salts include sodium, lithium, potassium, calcium,magnesium, and the like. Further pharmaceutically acceptable saltsinclude, when appropriate, nontoxic ammonium, quaternary ammonium, andamine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and arylsulfonate.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, Z and E double bond isomers,and Z and E conformational isomers. Therefore, single stereochemicalisomers as well as enantiomeric, diastereomeric, and geometric (orconformational) mixtures of the present compounds are within the scopeof the invention. Unless otherwise stated, all tautomeric forms of thecompounds of the invention are within the scope of the invention.

Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms.

For example, compounds having the present structures including thereplacement of hydrogen by deuterium or tritium, or the replacement of acarbon by a ¹³C- or ¹⁴C-enriched carbon are within the scope of thisinvention. In some embodiments, the group comprises one or moredeuterium atoms.

There is furthermore intended that a compound of the formula I includesisotope-labeled forms thereof. An isotope-labeled form of a compound ofthe formula I is identical to this compound apart from the fact that oneor more atoms of the compound have been replaced by an atom or atomshaving an atomic mass or mass number which differs from the atomic massor mass number of the atom which usually occurs naturally. Examples ofisotopes which are readily commercially available and which can beincorporated into a compound of the formula I by well-known methodsinclude isotopes of hydrogen, carbon, nitrogen, oxygen, phos-phorus,fluo-rine and chlorine, for example ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O,³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl, respectively. A compound of the formula I,a prodrug, thereof or a pharmaceutically acceptable salt of either whichcontains one or more of the above-mentioned isotopes and/or otherisotopes of other atoms is intended to be part of the present invention.An isotope-labeled compound of the formula I can be used in a number ofbeneficial ways. For example, an isotope-labeled compound of the formulaI into which, for example, a radioisotope, such as ³H or ¹⁴C, has beenincorporated, is suitable for medicament and/or substrate tissuedistribution assays. These radioisotopes, i.e. tritium (³H) andcarbon-14 (¹⁴C), are particularly preferred owing to simple preparationand excellent detectability. Incorporation of heavier isotopes, forexample deuterium (²H), into a compound of the formula I has therapeuticadvantages owing to the higher metabolic stability of thisisotope-labeled compound. Higher metabolic stability translates directlyinto an increased in vivo half-life or lower dosages, which under mostcircumstances would represent a preferred embodiment of the presentinvention. An isotope-labeled compound of the formula I can usually beprepared by carrying out the procedures disclosed in the synthesisschemes and the related description, in the example part and in thepreparation part in the present text, replacing a non-isotope-labeledreactant by a readily available isotope-labeled reactant.

Deuterium (²H) can also be incorporated into a compound of the formula Ifor the purpose in order to manipulate the oxidative metabolism of thecompound by way of the primary kinetic isotope effect. The primarykinetic isotope effect is a change of the rate for a chemical reactionthat results from exchange of isotopic nuclei, which in turn is causedby the change in ground state energies necessary for covalent bondformation after this isotopic exchange. Exchange of a heavier isotopeusually results in a lowering of the ground state energy for a chemicalbond and thus causes a reduction in the rate in rate-limiting bondbreakage. If the bond breakage occurs in or in the vicinity of asaddle-point region along the coordinate of a multi-product reaction,the product distribution ratios can be altered substantially. Forexplanation: if deuterium is bonded to a carbon atom at anon-exchangeable position, rate differences of k_(M)/k_(D)=2-7 aretypical. If this rate difference is successfully applied to a com-poundof the formula I that is susceptible to oxidation, the profile of thiscompound in vivo can be drastically modified and result in improvedpharmacokinetic properties.

When discovering and developing therapeutic agents, the person skilledin the art is able to optimize pharmacokinetic parameters whileretaining desirable in vitro properties. It is reasonable to assume thatmany compounds with poor pharmacokinetic profiles are susceptible tooxidative metabolism. In vitro liver microsomal assays currentlyavailable provide valuable information on the course of oxidativemetabolism of this type, which in turn permits the rational design ofdeuterated compounds of the formula I with improved stability throughresistance to such oxidative metabolism. Significant improvements in thepharmacokinetic profiles of compounds of the formula I are therebyobtained, and can be expressed quantitatively in terms of increases inthe in vivo half-life (t/2), concen-tra-tion at maximum therapeuticeffect (C_(max)), area under the dose response curve (AUC), and F; andin terms of reduced clearance, dose and materials costs.

The following is intended to illustrate the above: a compound of theformula I which has multiple potential sites of attack for oxidativemetabolism, for example benzylic hydrogen atoms and hydrogen atomsbonded to a nitrogen atom, is prepared as a series of analogues in whichvarious combinations of hydrogen atoms are replaced by deuterium atoms,so that some, most or all of these hydrogen atoms have been replaced bydeuterium atoms. Half-life determinations enable favorable and accuratedetermination of the extent of the extent to which the improvement inresistance to oxidative metabolism has improved. In this way, it isdetermined that the half-life of the parent compound can be extended byup to 100% as the result of deuterium-hydrogen exchange of this type.

Deuterium-hydrogen exchange in a compound of the formula I can also beused to achieve a favorable modification of the metabolite spectrum ofthe starting compound in order to diminish or eliminate undesired toxicmetabolites. For example, if a toxic metabolite arises through oxidativecarbon-hydrogen (C—H) bond cleavage, it can reasonably be assumed thatthe deuterated analogue will greatly diminish or eliminate production ofthe unwanted metabolite, even if the particular oxidation is not arate-determining step. Further information on the state of the art withrespect to deuterium-hydrogen exchange may be found, for example inHanzlik et al., J. Org. Chem. 55, 3992-3997, 1990, Reider et al., J.Org. Chem. 52, 3326-3334, 1987, Foster, Adv. Drug Res. 14, 1-40, 1985,Gillette et al, Biochemistry 33(10) 2927-2937, 1994, and Jarman et al.Carcinogenesis 16(4), 683-688, 1993.

As used herein, the term “modulator” is defined as a compound that bindsto and/or inhibits the target with measurable affinity. In certainembodiments, a modulator has an IC₅₀ and/or binding constant of lessabout 50 μM, less than about 1 μM, less than about 500 nM, less thanabout 100 nM, or less than about 10 nM.

The terms “measurable affinity” and “measurably inhibit,” as usedherein, means a measurable change in FSHR activity between a samplecomprising a compound of the present invention, or composition thereof,and FSHR, and an equivalent sample comprising FSHR, in the absence ofsaid compound, or composition thereof.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds. Theterm “stable”, as used herein, refers to compounds which possessstability sufficient to allow manufacture and which maintains theintegrity of the compound for a sufficient period of time to be usefulfor the purposes detailed herein (e.g., therapeutic or prophylacticadministration to a subject).

The recitation of a listing of chemical groups in any definition of avariable herein includes definitions of that variable as any singlegroup or combination of listed groups. The recitation of an embodimentfor a variable herein includes that embodiment as any single embodimentor in combination with any other embodiments or portions thereof.

3. Description of Exemplary Compounds

According to one aspect, the present invention provides a compound offormula I,

-   or a pharmaceutically acceptable salt thereof, wherein:-   X is O, S, SO, SO₂, or NR;-   Y is O, S, or NR;-   Z is O, S, SO, SO₂, or N; wherein when Z is O, S, SO, or SO₂, then p    is 0;-   each R is independently hydrogen, C₁₋₆ aliphatic, C₃₋₁₀ aryl, a 3-8    membered saturated or partially unsaturated carbocyclic ring, a 3-7    membered heterocylic ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, or sulfur, or a 5-6 membered    monocyclic heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, or sulfur; each of which is    optionally substituted; or-   two R groups on the same atom are taken together with the atom to    which they are attached to form a C₃₋₁₀ aryl, a 3-8 membered    saturated or partially unsaturated carbocyclic ring, a 3-7 membered    heterocylic ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl    ring having 1-4 heteroatoms independently selected from nitrogen,    oxygen, or sulfur; each of which is optionally substituted;-   Ring A is a fused C₃₋₁₀ aryl, a fused 3-8 membered saturated or    partially unsaturated carbocyclic ring, a fused 3-7 membered    heterocylic ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur, or a fused 5-6 membered monocyclic    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur;-   R¹ is —OR, —SR, —CN, —NO₂, —SO₂R, —SOR, —C(O)R, —CO₂R, —C(O)N(R)₂,    —NRC(O)R, —NRC(O)N(R)₂, —NRSO₂R, or —N(R)₂;-   R² is —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO₂, —SO₂R, —SOR,    —C(O)R, —CO₂R, —C(O)N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRSO₂R, or    —N(R)₂;-   R³ is hydrogen, C₁₋₆ aliphatic, C₃₋₁₀ aryl, a 3-8 membered saturated    or partially unsaturated carbocyclic ring, a 3-7 membered    heterocylic ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl    ring having 1-4 heteroatoms independently selected from nitrogen,    oxygen, or sulfur; each of which is optionally substituted;-   each R⁴ is independently —R, halogen, -haloalkyl, —OR, —SR, —CN,    —NO₂, —SO₂R, —SOR, —C(O)R, —CO₂R, —C(O)N(R)₂, —NRC(O)R,    —NRC(O)N(R)₂, —NRSO₂R, or —N(R)₂;-   R⁵ is C₁₋₆ aliphatic, C₃₋₁₀ aryl, a 3-8 membered saturated or    partially unsaturated carbocyclic ring, a 3-7 membered heterocylic    ring having 1-4 heteroatoms independently selected from nitrogen,    oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring    having 1-4 heteroatoms independently selected from nitrogen, oxygen,    or sulfur; each of which is optionally substituted;-   R⁶ is hydrogen, C₁₋₆ aliphatic, C₃₋₁₀ aryl, a 3-8 membered saturated    or partially unsaturated carbocyclic ring, a 3-7 membered    heterocylic ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl    ring having 1-4 heteroatoms independently selected from nitrogen,    oxygen, or sulfur; each of which is optionally substituted;-   or R⁵ and R⁶, together with the atom to which each is attached, form    a 3-8 membered heterocylic ring having 1-4 heteroatoms independently    selected from nitrogen, oxygen, or sulfur, or a 3-8 membered    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, oxygen, or sulfur; each of which is optionally    substituted;-   n is 0, 1, or 2; and-   p is 0 or 1.

In certain embodiments, X is O. In certain embodiments, X is S. Incertain embodiments, X is SO, or SO₂. In certain embodiments, X is NR.

In certain embodiments, Y is O. In certain embodiments, Y is S. Incertain embodiments, Y is NR.

In certain embodiments, Z is O. In certain embodiments, Z is S. Incertain embodiments, Z is SO or SO₂. In certain embodiments, Z is N.

In certain embodiments, Ring A is a fused C₃₋₁₀ aryl. In certainembodiments, Ring A is a fused 3-8 membered saturated or partiallyunsaturated carbocyclic ring. In certain embodiments, Ring A is a fused3-7 membered heterocylic ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In certain embodiments, RingA is a fused 5-6 membered monocyclic heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In certain embodiments, Ring A is phenyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, furanyl, furazanyl,imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl,isoxazolyl, morpholinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl; -1,2,5oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, piperazinyl, piperidinyl, purinyl,pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, tetrahydrofuranyl, thiazolyl, thienyl, thiophenyl, oxetanyl,or azetidinyl.

In certain embodiments, Ring A is phenyl.

In certain embodiments, R¹ is —OR, —SR, —SO₂R, —SOR, —C(O)R, —CO₂R,—C(O)N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRSO₂R, or —N(R)₂. In certainembodiments, R¹ is —OR, —SR, —SO₂R, or —SOR. In certain embodiments, R¹is —C(O)R, —CO₂R, or —C(O)N(R)₂. In certain embodiments, R¹ is —NRC(O)R,—NRC(O)N(R)₂, —NRSO₂R, or —N(R)₂.

In certain embodiments, R¹ is —OR, and R is hydrogen.

In certain embodiments, R¹ is —OR, and R is C₁₋₆ aliphatic, C₃₋₁₀ aryl,a 3-8 membered saturated or partially unsaturated carbocyclic ring, a3-7 membered heterocylic ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclicheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur; each of which is optionally substituted.

In certain embodiments, R¹ is —OR, and R is C₁₋₆ aliphatic. In certainembodiments, R is methyl, ethyl, propyl, i-propyl, butyl, s-butyl,t-butyl, straight or branched pentyl, or straight or branched hexyl;each of which is optionally substituted.

In certain embodiments, R¹ is —OR, and R is C₃₋₁₀ aryl, a 3-8 memberedsaturated or partially unsaturated carbocyclic ring, a 3-7 memberedheterocylic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

In certain embodiments, R is phenyl, naphthyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,[3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl,[2.2.2]bicyclooctanyl, fluorenyl, indanyl, tetrahydronaphthyl,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl,carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isoindolinyl, isoindolenyl,isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl,isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl; -1,2,5oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl,pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole,pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4thiadiazolyl, thianthrenyl, thiazolyl, thienyl,thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, oxetanyl, azetidinyl, or xanthenyl; each of which isoptionally substituted.

In certain embodiments, R² is hydrogen.

In certain embodiments, R² is C₁₋₆ aliphatic. In certain embodiments, R²is C₁₋₆ aliphatic wherein the aliphatic group is a C₁₋₆ alkyl. Incertain embodiments, R² is methyl, ethyl, propyl, i-propyl, butyl,s-butyl, t-butyl, straight or branched pentyl, or straight or branchedhexyl; each of which is optionally substituted. In certain embodiments,R² is C₁₋₆ aliphatic wherein the aliphatic group is a C₁₋₆ alkenyl.

In certain embodiments, R² is C₃₋₁₀ aryl, a 3-8 membered saturated orpartially unsaturated carbocyclic ring, a 3-7 membered heterocylic ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur;each of which is optionally substituted.

In certain embodiments, R² is phenyl, naphthyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,[3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl,[2.2.2]bicyclooctanyl, fluorenyl, indanyl, tetrahydronaphthyl,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl,carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isoindolinyl, isoindolenyl,isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl,isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl; -1,2,5oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl,pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole,pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4thiadiazolyl, thianthrenyl, thiazolyl, thienyl,thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, oxetanyl, azetidinyl, or xanthenyl; each of which isoptionally substituted.

In certain embodiments, R² is halogen, -haloalkyl, —OR, —SR, —CN, —NO₂,—SO₂R, —SOR, —C(O)R, —CO₂R, —C(O)N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRSO₂R,or —N(R)₂.

In certain embodiments, R² is F, Cl, Br, I, or haloalkyl.

In certain embodiments, R² is —OR, —SR, —CN, —NO₂, —SO₂R, —SOR, —C(O)R,—CO₂R, —C(O)N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRSO₂R, or —N(R)₂. Incertain embodiments, R is C₁ 6 aliphatic, C₃₋₁₀ aryl, a 3-8 memberedsaturated or partially unsaturated carbocyclic ring, a 3-7 memberedheterocylic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur; each of which is optionally substituted.

In certain embodiments, R is methyl, ethyl, propyl, i-propyl, butyl,s-butyl, t-butyl, straight or branched pentyl, or straight or branchedhexyl; each of which is optionally substituted. In other embodiments, Ris phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctanyl,[4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl, [2.2.2]bicyclooctanyl,fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, azocinyl,benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl,benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl,benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl,NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isoindolinyl, isoindolenyl,isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl,isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl; -1,2,5oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl,pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole,pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4thiadiazolyl, thianthrenyl, thiazolyl, thienyl,thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, oxetanyl, azetidinyl, or xanthenyl; each of which isoptionally substituted.

In certain embodiments, R² is hydrogen, Br, CN,

In certain embodiments, R² is

In certain embodiments, R² is

In certain embodiments, R² is

In certain embodiments, R³ is hydrogen.

In certain embodiments, R³ is C₁₋₆ aliphatic, C₃₋₁₀ aryl, a 3-8 memberedsaturated or partially unsaturated carbocyclic ring, a 3-7 memberedheterocylic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur; each of which is optionally substituted.

In certain embodiments, R³ is an optionally substituted C₁₋₆ aliphatic.In certain embodiments, R³ is an optionally substituted C₃₋₁₀ aryl. Incertain embodiments, R³ is an optionally substituted 3-8 memberedsaturated or partially unsaturated carbocyclic ring. In certainembodiments, R³ is an optionally substituted 3-7 membered heterocylicring having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. In certain embodiments, R³ is an optionallysubstituted 5-6 membered monocyclic heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In certain embodiments, is R³ is phenyl, naphthyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,[3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl,[2.2.2]bicyclooctanyl, fluorenyl, indanyl, tetrahydronaphthyl,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl,carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isoindolinyl, isoindolenyl,isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl,isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl; -1,2,5oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl,pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole,pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4thiadiazolyl, thianthrenyl, thiazolyl, thienyl,thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, oxetanyl, azetidinyl, or xanthenyl; each of which isoptionally substituted.

In certain embodiments, is R³ is dihydrofuro[2,3-b]tetrahydrofuran,furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl,1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl,isoindolinyl, isoindolenyl, isobenzofuranyl, isochromanyl, isoindazolyl,isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl,oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl; -1,2,5oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, purinyl,pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl,pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4thiadiazolyl, thianthrenyl, thiazolyl, thienyl,thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, or xanthenyl; each of which is optionally substituted.

In certain embodiments, R³ is

In certain embodiments, each R⁴ is independently hydrogen.

In certain embodiments, each R⁴ is independently C₁₋₆ aliphatic, C₃₋₁₀aryl, a 3-8 membered saturated or partially unsaturated carbocyclicring, a 3-7 membered heterocylic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or a 5-6membered monocyclic heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur; each of which is optionallysubstituted.

In certain embodiments, each R⁴ is independently an optionallysubstituted C₁₋₆ aliphatic. In certain embodiments, each R⁴ isindependently an optionally substituted C₃-10 aryl. In certainembodiments, each R⁴ is independently an optionally substituted 3-8membered saturated or partially unsaturated carbocyclic ring. In certainembodiments, each R⁴ is independently an optionally substituted 3-7membered heterocylic ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. In certain embodiments, each R⁴ isindependently an optionally substituted 5-6 membered monocyclicheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

In certain embodiments, each R⁴ is independently halogen, -haloalkyl,—OR, —SR, —CN, —NO₂, —SO₂R, —SOR, —C(O)R, —CO₂R, —C(O)N(R)₂, —NRC(O)R,—NRC(O)N(R)₂, —NRSO₂R, or —N(R)₂.

In certain embodiments, R⁵ is C₁₋₆ aliphatic, C₃₋₁₀ aryl, a 3-8 memberedsaturated or partially unsaturated carbocyclic ring, a 3-7 memberedheterocylic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur; each of which is optionally substituted.

In certain embodiments, R⁵ is an optionally substituted C₁₋₆ aliphatic.In certain embodiments, R⁵ is an optionally substituted C₃₋₁₀ aryl. Incertain embodiments, R⁵ is an optionally substituted 3-8 memberedsaturated or partially unsaturated carbocyclic ring. In certainembodiments, R⁵ is an optionally substituted 3-7 membered heterocylicring having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. In certain embodiments, R⁵ is an optionallysubstituted 5-6 membered monocyclic heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In certain embodiments, R⁵ is C₁₋₆ aliphatic. In certain embodiments, R⁵is methyl, ethyl, propyl, i-propyl, butyl, s-butyl, t-butyl, straight orbranched pentyl, or straight or branched hexyl; each of which isoptionally substituted

In certain embodiments, R⁵ is phenyl, naphthyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,[3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl,[2.2.2]bicyclooctanyl, fluorenyl, indanyl, tetrahydronaphthyl,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl,carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isoindolinyl, isoindolenyl,isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl,isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl; -1,2,5oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl,pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole,pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4thiadiazolyl, thianthrenyl, thiazolyl, thienyl,thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, oxetanyl, azetidinyl, or xanthenyl; each of which isoptionally substituted.

In certain embodiments, R⁵ and R⁶, together with the atom to which eachis attached, form a 3-8 membered heterocylic 1 ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, ora 5-6 membered heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur; each of which is optionallysubstituted.

In certain embodiments, R⁵ is methyl, t-butyl, or —CD₃.

In certain embodiments, R⁵ is

In certain embodiments, Z is N and the ring formed by Z, R⁵ and R⁶ is

In certain embodiments, R⁶ is hydrogen.

In certain embodiments, R⁶ is C₁₋₆ aliphatic, C₃-10 aryl, a 3-8 memberedsaturated or partially unsaturated carbocyclic ring, a 3-7 memberedheterocylic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur; each of which is optionally substituted.

In certain embodiments, R⁶ is an optionally substituted C₁₋₆ aliphatic.In certain embodiments, R⁶ is an optionally substituted C₃₋₁₀ aryl. Incertain embodiments, R⁶ is an optionally substituted 3-8 memberedsaturated or partially unsaturated carbocyclic ring. In certainembodiments, R⁶ is an optionally substituted 3-7 membered heterocylicring having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. In certain embodiments, R⁶ is an optionallysubstituted 5-6 membered monocyclic heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In certain embodiments, R⁶ is C₁₋₆ aliphatic. In certain embodiments, R⁶is methyl, ethyl, propyl, i-propyl, butyl, s-butyl, t-butyl, straight orbranched pentyl, or straight or branched hexyl; each of which isoptionally substituted.

In certain embodiments, R⁵ is phenyl, naphthyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,[3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl,[2.2.2]bicyclooctanyl, fluorenyl, indanyl, tetrahydronaphthyl,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl,carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isoindolinyl, isoindolenyl,isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl,isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl; -1,2,5oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl,pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole,pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4thiadiazolyl, thianthrenyl, thiazolyl, thienyl,thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, oxetanyl, azetidinyl, or xanthenyl; each of which isoptionally substituted.

In certain embodiments, R⁶ is hydrogen.

In certain embodiments, R⁶ is methyl, t-butyl, or —CD₃.

In certain embodiments, n is 0. In certain embodiments, n is 1. Incertain embodiments, n is 2.

In certain embodiments, p is 0. In certain embodiments, p is 1.

In certain embodiments, each of R¹, R², R³, R⁴, R⁵, R⁶, X, Y, Z, n, andp is as defined above and described in embodiments, classes andsubclasses above and herein, singly or in combination.

In certain embodiments, the present invention provides a compound offormula I-a,

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R²,R³, R⁵, R⁶, X, Y, Z, and p is as defined above and described inembodiments, classes and subclasses above and herein, singly or incombination.

In certain embodiments, the present invention provides a compound offormula I-b,

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R²,R³, R⁴, R⁵, R⁶, Y, Z, n, and p is as defined above and described inembodiments, classes and subclasses above and herein, singly or incombination.

In certain embodiments, the compound is of formula I-c:

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R²,R³, R⁵, R⁶, Z, and p is as defined above and described in embodiments,classes and subclasses above and herein, singly or in combination.

In certain embodiments, the invention provides a compound of formulaI-d:

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R²,R³, R⁵, and R⁶ is as defined above and described in embodiments, classesand subclasses above and herein, singly or in combination.

In certain embodiments, the invention provides a compound of formulaI-e:

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R²,R³, and R⁵ is as defined above and described in embodiments, classes andsubclasses above and herein, singly or in combination.

In other embodiments, the invention provides a compound of formula I-f:

or a pharmaceutically acceptable salt thereof, wherein each of R², R³,R⁵, and R⁶ is as defined above and described in embodiments, classes andsubclasses above and herein, singly or in combination.

In other embodiments, the invention provides a compound of formula I-g:

or a pharmaceutically acceptable salt thereof, wherein each of R², R³,and R⁵ is as defined above and described in embodiments, classes andsubclasses above and herein, singly or in combination.

In certain embodiments, the invention provides a compound of formulaI-h:

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R²,R⁵, R⁶, Z, and p is as defined above and described in embodiments,classes and subclasses above and herein, singly or in combination.

In certain embodiments, the invention provides a compound of formulaI-f, wherein R² is 5-6 membered monocyclic heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur;which is optionally substituted; R³ is an optionally substituted 5-6membered monocyclic heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur; and Z is N.

In certain embodiments, R⁵ is an optionally substituted C₁₋₆ aliphatic.

In certain embodiments, R⁵ and R⁶, together with the atom to which eachis attached, form a 3-8 membered heterocylic 1 ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur,which is optionally substituted.

In certain embodiments, R⁶ is an optionally substituted C₁₋₆ aliphatic.

In certain embodiments, the invention provides a compound of formulaI-h, wherein R¹ is —OR and R is C₁₋₆ aliphatic; R² is 5-6 memberedmonocyclic heteroaryl ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur; which is optionally substituted; and Zis N.

In certain embodiments, R⁵ is an optionally substituted C₁₋₆ aliphatic.

In certain embodiments, R⁵ and R⁶, together with the atom to which eachis attached, form a 3-8 membered heterocylic 1 ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur,which is optionally substituted.

In certain embodiments, R⁶ is an optionally substituted C₁₋₆ aliphatic.

In certain embodiments, the invention provides a compound selected fromTable 1:

TABLE 1

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

In some embodiments, the present invention provides a compound selectedfrom those depicted above, or a pharmaceutically acceptable saltthereof.

Various structural depictions may show a heteroatom without an attachedgroup, radical, charge, or counterion. Those of ordinary skill in theart are aware that such depictions are meant to indicate that theheteroatom is attached to hydrogen

is understood to be

In certain embodiments, the compounds of the invention were synthesizedin accordance with Schemes A-C below. More specific examples ofcompounds made utilizing Schemes A-C are provided in the Examples below.

4. Uses, Formulation and Administration

Pharmaceutically Acceptable Compositions

According to another embodiment, the invention provides a compositioncomprising a compound of this invention or a pharmaceutically acceptablederivative thereof and a pharmaceutically acceptable carrier, adjuvant,or vehicle. The amount of compound in compositions of this invention issuch that is effective to measurably modulate FSHR, or a mutant thereof,in a biological sample or in a patient. In certain embodiments, theamount of compound in compositions of this invention is such that iseffective to measurably modulate FSHR, or a mutant thereof, in abiological sample or in a patient. In certain embodiments, a compositionof this invention is formulated for administration to a patient in needof such composition.

The term “patient” or “subject”, as used herein, means an animal,preferably a mammal, and most preferably a human.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle”refers to a non-toxic carrier, adjuvant, or vehicle that does notdestroy the pharmacological activity of the compound with which it isformulated. Pharmaceutically acceptable carriers, adjuvants or vehiclesthat are used in the compositions of this invention include, but are notlimited to, ion exchangers, alumina, aluminum stearate, lecithin, serumproteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

A “pharmaceutically acceptable derivative” means any non-toxic salt,ester, salt of an ester or other derivative of a compound of thisinvention that, upon administration to a recipient, is capable ofproviding, either directly or indirectly, a compound of this inventionor an inhibitorily active metabolite or residue thereof.

Compositions of the present invention are administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir.

The term “parenteral” as used herein includes subcutaneous, intravenous,intramuscular, intra-articular, intra-synovial, intrasternal,intrathecal, intrahepatic, intralesional and intracranial injection orinfusion techniques. Preferably, the compositions are administeredorally, intraperitoneally or intravenously. Sterile injectable forms ofthe compositions of this invention include aqueous or oleaginoussuspension. These suspensions are formulated according to techniquesknown in the art using suitable dispersing or wetting agents andsuspending agents. The sterile injectable preparation is also be asterile injectable solution or suspension in a non-toxic parenterallyacceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that areemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium.

For this purpose, any bland fixed oil employed includes synthetic mono-or di-glycerides. Fatty acids, such as oleic acid and its glyceridederivatives are useful in the preparation of injectables, as are naturalpharmaceutically-acceptable oils, such as olive oil or castor oil,especially in their polyoxyethylated versions. These oil solutions orsuspensions also contain a long-chain alcohol diluent or dispersant,such as carboxymethyl cellulose or similar dispersing agents that arecommonly used in the formulation of pharmaceutically acceptable dosageforms including emulsions and suspensions. Other commonly usedsurfactants, such as Tweens, Spans and other emulsifying agents orbioavailability enhancers which are commonly used in the manufacture ofpharmaceutically acceptable solid, liquid, or other dosage forms arealso be used for the purposes of formulation.

Pharmaceutically acceptable compositions of this invention are orallyadministered in any orally acceptable dosage form. Exemplary oral dosageforms are capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include lactose andcorn starch. Lubricating agents, such as magnesium stearate, are alsotypically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents are optionally also added.

Alternatively, pharmaceutically acceptable compositions of thisinvention are administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient that is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

Pharmaceutically acceptable compositions of this invention are alsoadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches are also used.

For topical applications, provided pharmaceutically acceptablecompositions are formulated in a suitable ointment containing the activecomponent suspended or dissolved in one or more carriers. Exemplarycarriers for topical administration of compounds of this aremineral oil,liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene,polyoxypropylene compound, emulsifying wax and water. Alternatively,provided pharmaceutically acceptable compositions can be formulated in asuitable lotion or cream containing the active components suspended ordissolved in one or more pharmaceutically acceptable carriers. Suitablecarriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

Pharmaceutically acceptable compositions of this invention areoptionally administered by nasal aerosol or inhalation. Suchcompositions are prepared according to techniques well-known in the artof pharmaceutical formulation and are prepared as solutions in saline,employing benzyl alcohol or other suitable preservatives, absorptionpromoters to enhance bioavailability, fluorocarbons, and/or otherconventional solubilizing or dispersing agents.

Most preferably, pharmaceutically acceptable compositions of thisinvention are formulated for oral administration. Such formulations maybe administered with or without food. In some embodiments,pharmaceutically acceptable compositions of this invention areadministered without food. In other embodiments, pharmaceuticallyacceptable compositions of this invention are administered with food.

The amount of compounds of the present invention that are optionallycombined with the carrier materials to produce a composition in a singledosage form will vary depending upon the host treated, the particularmode of administration. Preferably, provided compositions should beformulated so that a dosage of between 0.01-100 mg/kg body weight/day ofthe compound can be administered to a patient receiving thesecompositions.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of a compound of the present invention in the composition willalso depend upon the particular compound in the composition.

Uses of Compounds and Pharmaceutically Acceptable Compositions

In certain embodiments, the invention provides a method forallosterically agonising FSHR, or a mutant thereof, in a positive mannerin a patient or in a biological sample comprising the step ofadministering to said patient or contacting said biological sample witha compound according to the invention.

In certain embodiments, the invention is directed to the use ofcompounds of the invention and/or physiologically acceptable saltsthereof, for modulating a FSH receptor, particularly in the presence ofFSH. The term “modulation” denotes any change in FSHR-mediated signaltransduction, which is based on the action of the specific inventivecompounds capable to interact with the FSHR target in such a manner thatmakes recognition, binding and activating possible. The compounds arecharacterized by such a high affinity to FSHR, which ensures a reliablebinding and preferably a positive allosteric modulation of FSHR. Incertain embodiments, the substances are mono-specific in order toguarantee an exclusive and directed recognition with the single FSHRtarget. In the context of the present invention, the term“recognition”—without being limited thereto—relates to any type ofinteraction between the specific compounds and the target, particularlycovalent or non-covalent binding or association, such as a covalentbond, hydrophobic/hydrophilic interactions, van der Waals forces, ionpairs, hydrogen bonds, ligand-receptor interactions, and the like. Suchassociation may also encompass the presence of other molecules such aspeptides, proteins or nucleotide sequences. The presentreceptor/ligand-interaction is characterized by high affinity, highselectivity and minimal or even lacking cross-reactivity to other targetmolecules to exclude unhealthy and harmful impacts to the treatedsubject.

In certain embodiments, the present invention relates to a method formodulating an FSH receptor, and in particular in a positive allostericmanner, wherein a system capable of expressing the FSH receptor iscontacted, in the presence of FSH, with at least one compound of formula(I) according to the invention and/or physiologically acceptable saltsthereof, under conditions such that said FSH receptor is modulated. Incertain embodiments, modulation is in a positive allosteric manner. Incertain embodiments, the system is a cellular system. In otherembodiments, the system is an in-vitro translation which is based on theprotein synthesis without living cells. The cellular system is definedto be any subject provided that the subject comprises cells. Hence, thecellular system can be selected from the group of single cells, cellcultures, tissues, organs and animals. In certain embodiments, themethod for modulating an FSH receptor is performed in-vitro. The priorteaching of the present specification concerning the compounds offormula (I), including any embodiments thereof, is valid and applicablewithout restrictions to the compounds according to formula (I) and theirsalts when used in the method for modulating FSHR. The prior teaching ofthe present specification concerning the compounds of formula (I),including any embodiments thereof, is valid and applicable withoutrestrictions to the compounds according to formula (I) and their saltswhen used in the method for modulating FSHR.

In certain embodiments, the compounds according to the invention exhibitan advantageous biological activity, which is easily demonstrated incell culture-based assays, for example assays as described herein or inprior art (cf. e.g. WO 2002/09706, which is incorporated herein byreference). In such assays, the compounds according to the inventionpreferably exhibit and cause an agonistic effect. In certainembodiments, the compounds of the invention have an FSHR agonistactivity, as expressed by an EC₅₀ standard, of less than 5 μM. Incertain embodiments, less than 1 μM. In certain embodiments, less than0.5 μM. In certain embodiments, less than 0.1 μM. “EC₅₀” is theeffective concentration of a compound at which 50% of the maximalresponse of that obtained with FSH would be obtained.

As discussed herein, these signaling pathways are relevant for variousdiseases, including fertility disorders. Disorders/diseases treated bythe methods of the invention include but are not limited to,hypogonadotropic hypogonadism, Isolated idiopathic hypogonadotropichypogonadism, Kallmann syndrome, Idiopathic hypogonadotropichypogonadism, Craniopharyngiomas, Combined pituitary hormone deficiency,Fertile eunuch syndrome, Abnormal beta subunit of LH, Abnormal betasubunit of FSH, mass lesions, pituitary adenomas, cysts, metastaticcancer to the sella (breast in women, lung and prostate in men),Infiltrative lesions, Hemochromatosis, sarcoidosis, histiocytosis,lymphoma, Lymphocytic hypophysitis, Infections, Meningitis, Pituitaryapoplexy, Hyperprolactinemia, hypothyroidism, Intentional (iatrogenic)secondary hypogonadism, Empty sella, Pituitary infarction, Sheehansyndrome, Anorexia nervosa, Congenital adrenal hyperplasia, anddisorders related to GnRH deficiency. Accordingly, the compoundsaccording to the invention are useful in the prophylaxis and/ortreatment of diseases that are dependent on the said signaling pathwaysby interaction with one or more of the said signaling pathways. Thepresent invention therefore relates to compounds according to theinvention as modulators, preferably agonists, more preferably positiveallosteric modulators, of the signaling pathways described herein,preferably of the FSHR-mediated signaling pathway. The compounds of theinvention are supposed to bind to the intracellular receptor domainwithout a competitive interaction with FSH, but they act as anallosteric enhancer of FSH on its receptor. The non-competitiveinteraction refers to the nature of the agonist activity exhibited bythe compounds of the invention, wherein the compounds activate FSHRwithout substantially reducing the magnitude of binding of FSH to FSHR.

In certain embodiments, the invention is directed towards thestimulation of follicular development, ovulation induction, controlledovarial hyperstimulation, assisted reproductive technology, includingin-vitro fertilization, male hypogonadism and male infertility,including some types of failure of spermatogenesis.

It is another object of the invention to provide a method for treatingdiseases that are caused, mediated and/or propagated by FSHR activity,wherein at least one compound of formula (I) according to the inventionand/or physiologically acceptable salts thereof is administered to amammal in need of such treatment. In certain embodiments, the inventionprovides a method for treating fertility disorders, wherein at least onecompound of formula (I) according to the invention and/orphysiologically acceptable salts thereof is administered to a mammal inneed of such treatment. In certain embodiments, the compound isadministered in an effective amount as defined above. In certainembodiments, the treatment is an oral administration.

In certain embodiments, the method of treatment aims to achieveovulation induction and/or controlled ovarian hyperstimulation. In stillanother embodiment, the method of treatment forms the basis for a methodfor in-vitro fertilization comprising the steps of: (a) treating amammal according to the method of treatment as described above, (b)collecting ova from said mammal, (c) fertilizing said ova, and (d)implanting said fertilized ova into a host mammal. The host mammal canbe either the treated mammal (i.e. the patient) or a surrogate. Theprior teaching of the invention and its embodiments is valid andapplicable without restrictions to the methods of treatment ifexpedient.

The method of the invention can be performed either in-vitro or in-vivo.The susceptibility of a particular cell to treatment with the compoundsaccording to the invention can be particularly determined by in-vitrotests, whether in the course of research or clinical application.Typically, a culture of the cell is combined with a compound accordingto the invention at various concentrations for a period of time which issufficient to allow the active agents to modulate FSHR activity, usuallybetween about one hour and one week. In-vitro treatment can be carriedout using cultivated cells from a biopsy sample or cell line. In apreferred aspect of the invention, a follicle cell is stimulated formaturation. The viable cells remaining after the treatment are countedand further processed.

The host or patient can belong to any mammalian species, for example aprimate species, particularly humans; rodents, including mice, rats andhamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are ofinterest for experimental investigations, providing a model fortreatment of human disease.

For identification of a signal transduction pathway and for detection ofinteractions between various signal transduction pathways, variousscientists have developed suitable models or model systems, for examplecell culture models and models of transgenic animals. For thedetermination of certain stages in the signal transduction cascade,interacting compounds can be utilized in order to modulate the signal.The compounds according to the invention can also be used as reagentsfor testing FSHR-dependent signal transduction pathways in animalsand/or cell culture models or in the clinical diseases mentioned in thisapplication.

The use according to the previous paragraphs of the specification may beeither performed in-vitro or in-vivo models. The modulation can bemonitored by the techniques described in the course of the presentspecification. In certain embodiments, the in-vitro use is preferablyapplied to samples of humans suffering from fertility disorders. Testingof several specific compounds and/or derivatives thereof makes theselection of that active ingredient possible that is best suited for thetreatment of the human subject. The in-vivo dose rate of the chosenderivative is advantageously pre-adjusted to the FSHR susceptibilityand/or severity of disease of the respective subject with regard to thein-vitro data. Therefore, the therapeutic efficacy is remarkablyenhanced. Moreover, the subsequent teaching of the present specificationconcerning the use of the compounds according to formula (I) and itsderivatives for the production of a medicament for the prophylactic ortherapeutic treatment and/or monitoring is considered as valid andapplicable without restrictions to the use of the compound for themodulation of FSHR activity if expedient.

The invention also relates to the use of compounds according to formula(I) and/or physiologically acceptable salts thereof for the prophylacticor therapeutic treatment and/or monitoring of diseases that are caused,mediated and/or propagated by FSHR activity. Furthermore, the inventionrelates to the use of compounds according to formula (I) and/orphysiologically acceptable salts thereof for the production of amedicament for the prophylactic or therapeutic treatment and/ormonitoring of diseases that are caused, mediated and/or propagated byFSHR activity. In certain embodiments, the invention provides the use ofa compound according to formula I or physiologically acceptable saltsthereof, for the production of a medicament for the prophylactic ortherapeutic treatment of a FSHR-mediated disorder.

Compounds of formula (I) and/or a physiologically acceptable saltthereof can furthermore be employed as intermediate for the preparationof further medicament active ingredients. The medicament is preferablyprepared in a non-chemical manner, e.g. by combining the activeingredient with at least one solid, fluid and/or semi-fluid carrier orexcipient, and optionally in conjunction with a single or more otheractive substances in an appropriate dosage form.

Another object of the present invention are compounds of formula (I)according to the invention and/or physiologically acceptable saltsthereof for use in the prophylactic or therapeutic treatment and/ormonitoring of diseases that are caused, mediated and/or propagated byFSHR activity. Another preferred object of the invention concernscompounds of formula (I) according to the invention and/orphysiologically acceptable salts thereof for use in the prophylactic ortherapeutic treatment and/or monitoring of fertility disorders. Theprior teaching of the present specification concerning the compounds offormula (I), including any preferred embodiment thereof, is valid andapplicable without restrictions to the compounds according to formula(I) and their salts for use in the prophylactic or therapeutic treatmentand/or monitoring of fertility disorders.

The compounds of formula (I) according to the invention can beadministered before or following an onset of disease once or severaltimes acting as therapy. The aforementioned compounds and medicalproducts of the inventive use are particularly used for the therapeutictreatment. A therapeutically relevant effect relieves to some extent oneor more symptoms of a disorder, or returns to normality, eitherpartially or completely, one or more physiological or biochemicalparameters associated with or causative of a disease or pathologicalcondition. Monitoring is considered as a kind of treatment provided thatthe compounds are administered in distinct intervals, e.g. in order tobooster the response and eradicate the pathogens and/or symptoms of thedisease completely. Either the identical compound or different compoundscan be applied. The methods of the invention can also be used toreducing the likelihood of developing a disorder or even prevent theinitiation of disorders associated with FSHR activity in advance or totreat the arising and continuing symptoms. In certain embodiments, thedisorders are fertility disorders.

In the meaning of the invention, prophylactic treatment is advisable ifthe subject possesses any preconditions for the aforementionedphysiological or pathological conditions, such as a familialdisposition, a genetic defect, or a previously passed disease.

The invention furthermore relates to a medicament comprising at leastone compound according to the invention and/or pharmaceutically usablederivatives, salts, solvates and stereoisomers thereof, includingmixtures thereof in all ratios. In certain embodiments, the inventionrelates to a medicament comprising at least one compound according tothe invention and/or physiologically acceptable salts thereof.

A “medicament” in the meaning of the invention is any agent in the fieldof medicine, which comprises one or more compounds of formula (I) orpreparations thereof (e.g. a pharmaceutical composition orpharmaceutical formulation) and can be used in prophylaxis, therapy,follow-up or aftercare of patients who suffer from diseases, which areassociated with FSHR activity, in such a way that a pathogenicmodification of their overall condition or of the condition ofparticular regions of the organism could establish at least temporarily.

In various embodiments, the active ingredient may be administered aloneor in combination with other treatments. A synergistic effect may beachieved by using more than one compound in the pharmaceuticalcomposition, i.e. the compound of formula (I) is combined with at leastanother agent as active ingredient, which is either another compound offormula (I) or a compound of different structural scaffold. The activeingredients can be used either simultaneously or sequentially. Thepresent compounds are suitable for combination with knownfertility-inducing agents. In certain embodiments, the other activepharmaceutical ingredient is selected from the group of FSH, α-FSH(Gonal F), β-FSH, LH, hMG and2-(4-(2-chloro-1,2-diphenylethenyl)-phenoxy)-N,N-diethyl-ethanaminecitrate (Chlomifene citrate). Further ovulation adjuncts are known tothose of skill in the art (cf. e.g. WO 2002/09706, which is incorporatedherein by reference) and are useful with the compounds of the presentinvention.

In another aspect, the invention provides for a kit consisting ofseparate packs of an effective amount of a compound according to theinvention and/or pharmaceutically acceptable salts, derivatives,solvates and stereoisomers thereof, including mixtures thereof in allratios, and optionally, an effective amount of a further activeingredient. The kit comprises suitable containers, such as boxes,individual bottles, bags or ampoules. The kit may, for example, compriseseparate ampoules, each containing an effective amount of a compoundaccording to the invention and/or pharmaceutically acceptable salts,derivatives, solvates and stereoisomers thereof, including mixturesthereof in all ratios, and an effective amount of a further activeingredient in dissolved or lyophilized form.

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, or inhibiting theprogress of a disease or disorder, or one or more symptoms thereof, asdescribed herein. In some embodiments, treatment is administered afterone or more symptoms have developed. In other embodiments, treatment isadministered in the absence of symptoms. For example, treatment isadministered to a susceptible individual prior to the onset of symptoms(e.g., in light of a history of symptoms and/or in light of genetic orother susceptibility factors). Treatment is also continued aftersymptoms have resolved, for example to prevent or delay theirrecurrence.

The compounds and compositions, according to the method of the presentinvention, are administered using any amount and any route ofadministration effective for treating or lessening the severity of adisorder provided above. The exact amount required will vary fromsubject to subject, depending on the species, age, and general conditionof the subject, the severity of the infection, the particular agent, itsmode of administration, and the like.

Compounds of the invention are preferably formulated in dosage unit formfor ease of administration and uniformity of dosage. The expression“dosage unit form” as used herein refers to a physically discrete unitof agent appropriate for the patient to be treated. It will beunderstood, however, that the total daily usage of the compounds andcompositions of the present invention will be decided by the attendingphysician within the scope of sound medical judgment. The specificeffective dose level for any particular patient or organism will dependupon a variety of factors including the disorder being treated and theseverity of the disorder; the activity of the specific compoundemployed; the specific composition employed; the age, body weight,general health, sex and diet of the patient; the time of administration,route of administration, and rate of excretion of the specific compoundemployed; the duration of the treatment; drugs used in combination orcoincidental with the specific compound employed, and like factors wellknown in the medical arts.

Pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention are administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 100mg/kg and preferably from about 1 mg/kg to about 50 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms optionally contain inert diluents commonly usedin the art such as, for example, water or other solvents, solubilizingagents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions are formulated according to the known art usingsuitable dispersing or wetting agents and suspending agents. The sterileinjectable preparation are also a sterile injectable solution,suspension or emulsion in a nontoxic parenterally acceptable diluent orsolvent, for example, as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Injectable formulations can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or other sterile injectable medium priorto use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection.

This is accomplished by the use of a liquid suspension of crystalline oramorphous material with poor water solubility. The rate of absorption ofthe compound then depends upon its rate of dissolution that, in turn,may depend upon crystal size and crystalline form. Alternatively,delayed absorption of a parenterally administered compound form isaccomplished by dissolving or suspending the compound in an oil vehicle.Injectable depot forms are made by forming microencapsule matrices ofthe compound in biodegradable polymers such aspolylactide-polyglycolide. Depending upon the ratio of compound topolymer and the nature of the particular polymer employed, the rate ofcompound release can be controlled. Examples of other biodegradablepolymers include poly(orthoesters) and poly(anhydrides). Depotinjectable formulations are also prepared by entrapping the compound inliposomes or microemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form also optionally comprises buffering agents.

Solid compositions of a similar type are also employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype are also employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms optionally also comprisebuffering agents. They optionally contain opacifying agents and can alsobe of a composition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as required. Ophthalmicformulation, ear drops, and eye drops are also contemplated as beingwithin the scope of this invention.

Additionally, the present invention contemplates the use of transdermalpatches, which have the added advantage of providing controlled deliveryof a compound to the body. Such dosage forms can be made by dissolvingor dispensing the compound in the proper medium. Absorption enhancerscan also be used to increase the flux of the compound across the skin.The rate can be controlled by either providing a rate controllingmembrane or by dispersing the compound in a polymer matrix or gel.

According to one embodiment, the invention relates to a method ofallosterically modulating FSHR activity in a biological samplecomprising the step of contacting said biological sample with a compoundof this invention, or a composition comprising said compound.

According to another embodiment, the invention relates to a method ofallosterically modulating FSHR, or a mutant thereof, activity in abiological sample in a positive manner, comprising the step ofcontacting said biological sample with a compound of this invention, ora composition comprising said compound.

The compounds of the invention are strong and selective modulators ofthe FSH receptor. Their selectivity to the FSH receptor is 3 to 10-foldover the LH receptor and even 10 to 100-fold over the TSH receptor whilethe EC₅₀ or IC₅₀ amounts to more than 10 μM on unrelated Gprotein-coupled receptors (GPCR) or non-GPCR targets. The currentinvention comprises the use of the compounds of the invention in theregulation and/or modulation of the FSHR signal cascade, which can beadvantageously applied as research tool, for diagnosis and/or intreatment of any disorder arising from FSHR signaling.

For example, the compounds of the invention are useful in-vitro asunique tools for understanding the biological role of FSH, including theevaluation of the many factors thought to influence, and be influencedby, the production of FSH and the interaction of FSH with the FSHR (e.g. the mechanism of FSH signal transduction/receptor activation). Thepresent compounds are also useful in the development of other compoundsthat interact with FSHR since the present compounds provide importantstructure-activity relationship (SAR) information that facilitate thatdevelopment. Compounds of the present invention that bind to FSHR can beused as reagents for detecting FSHR on living cells, fixed cells, inbiological fluids, in tissue homogenates, in purified, naturalbiological materials, etc. For example, by labeling such compounds, onecan identify cells having FSHR on their surfaces. In addition, based ontheir ability to bind FSHR, compounds of the present invention can beused in in-situ staining, FACS (fluorescence-activated cell sorting),western blotting, ELISA (enzyme-linked immunoadsorptive assay), etc.,receptor purification, or in purifying cells expressing FSHR on the cellsurface or inside permeabilized cells.

The compounds of the invention can also be utilized as commercialresearch reagents for various medical research and diagnostic uses. Suchuses can include but are not limited to: use as a calibration standardfor quantifying the activities of candidate FSH agonists in a variety offunctional assays; use as blocking reagents in random compoundscreening, i.e. in looking for new families of FSH receptor ligands, thecompounds can be used to block recovery of the presently claimed FSHcompounds; use in the co-crystallization with FSHR receptor, i.e. thecompounds of the present invention will allow formation of crystals ofthe compound bound to FSHR, enabling the determination ofreceptor/compound structure by x-ray crystallography; other research anddiagnostic applications, wherein FSHR is preferably activated or suchactivation is conveniently calibrated against a known quantity of an FSHagonist, etc.; use in assays as probes for determining the expression ofFSHR on the surface of cells; and developing assays for detectingcompounds which bind to the same site as the FSHR binding ligands.

The compounds of the invention can be applied either themselves and/orin combination with physical measurements for diagnostics of treatmenteffectiveness. Pharmaceutical compositions containing said compounds andthe use of said compounds to treat FSHR-mediated conditions is apromising, novel approach for a broad spectrum of therapies causing adirect and immediate improvement in the state of health, whether inhuman or animal. The impact is of special benefit to efficiently combatinfertility, either alone or in combination with otherfertility-inducing treatments. In particular, the compounds of theinvention potentiate the native FSH effect for both ovulation inductionand assisted reproductive technology. The orally bioavailable and activenew chemical entities of the invention improve convenience for patientsand compliance for physicians.

The compounds of the invention are active in the primary screen (CHOwith or without FSH), selective in secondary screen (no or low activityagainst TSHR and LHR) and potent in the granulosa cell estrodiol assay.Neither hERG nor any toxic effects could be observed in-vitro.

In certain embodiments, the invention provides a method for in-vitrofertilization comprising the steps of:

(a) treating a mammal according to the method as described above,

(b) collecting ova from said mammal,

(c) fertilizing said ova, and

(d) implanting said fertilized ova into a host mammal.

The compounds of formula (I), their salts, isomers, tautomers,enantiomeric forms, diastereomers, racemates, derivatives, prodrugsand/or metabolites are characterized by a high specificity andstability, low manufacturing costs and convenient handling. Thesefeatures form the basis for a reproducible action, wherein the lack ofcross-reactivity is included, and for a reliable and safe interactionwith the target structure.

The term “biological sample”, as used herein, includes, withoutlimitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof; and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

Modulation of FSHR, or a mutant thereof, activity in a biological sampleis useful for a variety of purposes that are known to one of skill inthe art. Examples of such purposes include, but are not limited to,blood transfusion, organ transplantation, biological specimen storage,and biological assays.

EXEMPLIFICATION

As depicted in the Examples below, in certain exemplary embodiments,compounds are prepared according to the following general procedures. Itwill be appreciated that, although the general methods depict thesynthesis of certain compounds of the present invention, the followinggeneral methods, and other methods known to one of ordinary skill in theart, can be applied to all compounds and subclasses and species of eachof these compounds, as described herein.

Compound numbers utilized in the Examples below correspond to compoundnumbers set forth supra.

¹H NMR was recorded on a Bruker 400 MHz spectrometer, using residualsignal of deuterated solvent as internal reference. Chemical shifts (δ)are reported in ppm relative to the residual solvent signal (δ=2.49 ppmfor 1H NMR in DMSO-d6). 1H NMR data are reported as follows: chemicalshift (multiplicity, coupling constants, and number of hydrogens).Multiplicity is abbreviated as follows: s (singlet), d (doublet), t(triplet), q (quartet), m (multiplet), br (broad).

LCMS-Analysis was performed under the following conditions:

Method: A: 0.1% TFA in H₂O, B: 0.1% TFA in ACN:

Runtime: 6.5 min

Flow Rate: 1.0 mL/min

Gradient: 5-95% B in 4.5 min, wavelength 254 and 215 nM.

Column: Waters Sunfire C18, 3.0×50 mm, 3.5 um, +ve mode

Mass Scan: 100-900 Da

Example 17-Methoxy-8-(1H-pyrazol-4-yl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid tert-butyl-methyl-amide (1) Step 1:3-Bromo-1-(2,4-dihydroxyphenyl)propan-1-one

To a stirred suspension of resorcinol (25 g, 0.22 mol) and3-Bromopropanoic acid (38.3 g, 0.25 mol) was addedtrifluoromethanesulfonic acid (75 mL, 0.84 mol) drop wise at 0° C. undernitrogen atmosphere. After the addition, the reaction mixture was heatedto 80° C. for 30 min. The reaction mixture was cooled to RT and quenchedwith ice water (200 mL) and extracted with DCM (500 mL). The aqueouslayer was re-extracted with DCM (2×100 mL); the combined organic layerwas dried over sodium sulphate and concentrated under vacuum to affordthe desired compound (40 g, 72%) as an orange solid.

¹H NMR (400 MHz, DMSO-d₆) δ 12.2 (bs, 1H), 10.6 (bs, 1H), 7.77-7.75 (d,J=8 Hz, 1H), 6.38-6.35 (dd, J=2.0, 8.8 Hz, 1H), 6.26-6.26 (d, J=4.0 Hz,1H), 3.74 (t, J=6.8 Hz, 2H), 3.61-3.57 (dd, J=6.0, 11.2 Hz, 2H).

Step 2: 7-Hydroxy-2,3-dihydro-4H-chromen-4-one

To an ice cold solution of 2M NaOH (92 mL, 2.33 mol), was added3-Bromo-1-(2,4-dihydroxyphenyl)propan-1-one (38 g, 0.155 mol) in lotsover a period of 30 min. The resulting suspension was stirred at RT for2 h. The reaction mixture was cooled to 0° C.; pH was adjusted to ˜2using 50% aqueous solution of sulfuric acid. The solid separated out wasstirred for additional 10 min at RT, filtered and dried under highvacuum to afford the desired compound (16 g, 63%) as brown solid.

¹H NMR (400 MHz, DMSO-d₆) δ 10.52 (bs, 1H), 7.61-7.59 (d, J=8.0 Hz, 1H),6.48-6.45 (dd, J=4.0, 12.0 Hz, 1H), 6.29-6.20 (d, J=4.0 Hz, 1H), 4.44(t, J=4.0 Hz, 2H), 2.65 (t, J=4.0 Hz, 2H).

Step 3: 7-Methoxy-2,3-dihydro-4H-chromen-4-one

To a stirred solution of 7-Hydroxy-2,3-dihydro-4H-chromen-4-one (27 g,0.16 mol) in acetone (700 mL) was added dry K₂CO₃ (45.6 g, 0.32 mol) inlots at RT under nitrogen. The reaction mixture was stirred at RT for 10min and then methyl iodide (65.4 g, 0.46 mol) was added drop wise at RT.The reaction mixture was stirred at RT for 4 h. The reaction mixture wasfiltered and filtrate was concentrated under vacuum. The crude productwas dissolved in DCM (200 mL), washed with water (100 mL), brine (50mL), dried over sodium sulphate and concentrated under vacuum to affordthe desired compound (15 g, 89%) as light yellow solid.

¹H NMR (400 MHz, CDCl₃) δ 7.85-7.83 (d, J=8.0 Hz, 1H), 6.60-6.57 (dd,J=4.0, 12.0 Hz, 1H), 6.41-6.41 (d, J=4.0 Hz, 1H), 4.52 (t, J=8.0 Hz,2H), 3.77 (s, 3H), 2.76 (t, J=4.0 Hz, 2H).

Step 4: 6-Bromo-7-methoxy-2,3-dihydro-4H-chromen-4-one

To a solution of 7-Methoxy-2,3-dihydro-4H-chromen-4-one (30 g, 0.16 mol)in acetonitrile:diethyl ether mixture (100:300 mL) was added silica gel60-120 mesh (1.5 g) and NBS (33 g, 0.18 mol) in lots at RT undernitrogen. The reaction mixture was stirred at RT for 14 h. The reactionmixture was filtered and concentrated under vacuum. The crude productwas purified by column chromatography by using pet ether/ethyl acetate(9:1) as eluent to afford the desired compound (10 g, 72%) as a lightbrown solid.

¹H NMR (400 MHz, DMSO-d₆) δ 7.82 (s, 1H), 6.73 (s, 1H), 4.53 (t, J=8.0Hz, 2H), 3.89 (s, 3H), 2.72 (t, J=8.0 Hz, 2H).

Step 5:Ethyl-(6-bromo-7-methoxy-4-oxo-2H-chromen-3(4H)-ylidene)(hydroxy)acetate

Diisopropylamine (7 mL, 0.3958 mol) was taken in dry THF (50 mL) at RTunder nitrogen atmosphere. The reaction mixture was cooled to −78° C.and n-Butyl lithium (1.6 M solution in hexane, 29.2 mL, 0.04 mol) wasadded drop wise over a period of 30 min. After the addition, thereaction mixture was stirred at the same temperature for 15 min and thenslowly warmed to −10° C. and stirred further for 30 min. The reactionmixture was again cooled to −78° C.,6-Bromo-7-methoxy-2,3-dihydro-4H-chromen-4-one (10 g, 0.03 mol) in THF(50 mL) was added drop wise over period of 30 min and stirred at −78° C.After 1 h, diethyl oxalate (7.8 mL, 0.05 mol) was added drop wise at−78° C.; the reaction mixture was slowly brought to 0° C. and stirredfor 1 h. The reaction mixture was cooled to −5° C., quenched with asolution of 1.5N HCl and extracted with ethyl acetate (100 mL×2). Thecombined organic layer was washed with water (100 mL), brine (50 mL),dried over sodium sulphate and concentrated to afford the desiredcompound (10 g, 72%) as pale yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ. 8.04 (s, 1H), 6.43 (s, 1H), 5.32 (s, 2H),4.40-4.32 (m, 2H), 3.95 (s, 3H), 1.42-1.37 (m, 3H).

Step 6: tert-Butyl 1-(3-thienyl)hydrazinecarboxylate

To a solution of 3-Bromo thiophene (10 g, 0.061 mol) in DMSO (100 mL)was added tert-butyl carbazate (16.3 g, 0.122 mol), cesium carbonate (40g, 0.122 mol) followed by CuI (1.2 g, 0.006 mol) and 4-Hydroxy-L-Proline(1.6 g, 0.01 mol) at RT under nitrogen. The reaction mixture was stirredat 80° C. for 14 h. The reaction mixture was cooled to RT, quenched withwater (100 mL) and extracted with ethyl acetate (3×200 mL). The combinedorganic layer was washed with water (100 mL×2), brine (100 mL), driedover sodium sulphate and evaporated under vacuum. The crude product waspurified by column chromatography by using pet ether and ethyl acetate(7:3) as eluent to afford the title compound (3.5 g, 27%) as pale brownliquid.

¹H NMR (400 MHz, DMSO-d₆) δ 7.37-7.35 (dd, J=4.0, 5.2 Hz, 1H), 7.31-7.29(d, J=8.0 Hz, 1H), 7.14-7.13 (dd, J=4.0, 5.2 Hz, 1H), 5.09 (bs, 2H),1.47 (s, 9H).

Step 7: 3-Thienylhydrazine hydrochloride

To a stirred solution of tert-Butyl 1-(3-thienyl)hydrazinecarboxylate(3.5 g, 0.0163 mol) in diethyl ether (10 mL) was added HCl in dioxane(30 mL) at RT under nitrogen. The reaction mixture was stirred at RT for8 h. The organic solvent was removed under reduced pressure to affordthe desired compound (2.4 g, 97%) as pale brown solid.

¹H NMR (400 MHz, DMSO-d₆) δ 10.08 (bs, 3H), 8.20 (bs, 1H), 7.48-7.46(dd, J=3.2, 5.2 Hz, 1H), 6.87-6.85 (dd, J=1.2, 4.8 Hz, 1H), 6.72-6.71(dd, J=1.6, 3.2 Hz, 1H).

Step 8: Ethyl8-bromo-7-methoxy-1-(3-thienyl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate

To a solution ofethyl-(6-bromo-7-methoxy-4-oxo-2H-chromen-3(4H)-ylidene)(hydroxy)acetate(8.0 g, 0.0224 mol) in a mixture of ethanol (200 mL) and acetic acid(200 mL) was added 3-thienylhydrazine hydrochloride (4.4 g, 0.0291 mol)at RT under nitrogen. The reaction mixture was stirred at 100° C. for 4h. The reaction mixture was concentrated under high vacuum. The residuewas dissolved with ethyl acetate (40 mL), washed with water (20 mL),brine (20 mL), dried over sodium sulphate and concentrated under vacuum.The crude product was purified by column chromatography using petether/ethyl acetate as eluent to afford the desired compound (8.5 g,87%) as a pale yellow solid.

¹H NMR (400 MHz, CDCl₃) δ 7.57-7.55 (dd, J=4.0, 5.2 Hz, 1H), 7.52-7.50(dd, J=4.0, 5.2 Hz, 1H), 7.22-7.21 (dd, J=1.2, 5.2 Hz, 1H), 6.94 (s,1H), 6.60 (s, 1H), 5.56 (s, 2H), 4.47-4.41 (dd, J=8.0, 12 Hz. 2H), 3.88(s, 3H), 1.42 (t, J=8.0 Hz, 3H).

Step 9:8-Bromo-7-methoxy-1-(3-thienyl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylicacid

To a solution of Ethyl8-bromo-7-methoxy-1-(3-thienyl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate(3 g, 0.0069 mol) in mixture of THF (70 mL), H₂O (20 mL), MeOH (10 mL)was added LiOH.H₂O (0.857 g, 0.0207 mol) at RT. The reaction mixture wasstirred at RT for 4 h. The reaction mixture was evaporated and acidifiedwith a solution of 1.5N HCl. The solid was filtered and dried to affordthe desired compound (2.8 g, 99%) as an off-white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 13.28 (bs, 1H), 8.01-8.00 (dd, J=1.2, 5.2Hz, 1H), 7.87-7.85 (dd, J=4.0, 5.2 Hz, 1H), 7.35-7.33 (dd, J=4.0, 8.0Hz, 1H), 6.83 (s, 1H), 6.73 (s, 1H), 5.50 (s, 2H), 3.82 (s, 3H). m/z:407 [M+H]⁺

Step 10:8-Bromo-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid tert-butyl-methyl-amide (4)

To a solution of 8-bromo-7-methoxy-1-(3-thienyl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylic acid (2.8 g, 0.0069 mol) in DCM (50 mL) wasadded N-tert-butyl methyl amine (718 mg, 0.0083 mol), HATU (3.14 g,0.0083 mol) and diisopropyl ethyl amine (1.8 mL, 0.0103 mol) at RT undernitrogen. The reaction mixture was stirred at RT for 16 h. The reactionmixture was quenched to sodium bicarbonate (10 mL, 10%), extracted withDCM (2×50 mL). The combined organic layer was washed with NaHCO₃solution (1×100 mL, 10% solution), brine (100 mL) and dried overanhydrous sodium sulphate. The solvent was removed under vacuum; thecrude product was purified by column chromatography by using pet etherand ethyl acetate (9:1) as eluent to afford the desired compound (3.2 g,98%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 7.98-7.97 (dd, J=1.4, 3.2 Hz, 1H), 7.80-7.85(dd, J=3.2, 4.7 Hz, 1H), 7.33-7.32 (dd, J=1.3, 5.1 Hz, 1H), 6.83 (s,1H), 6.76 (s, 1H), 5.37 (s, 2H), 3.81 (s, 3H), 3.15 (s, 3H), 1.47 (s,9H). m/z: 476 [M+H]⁺

Step 11:7-Methoxy-8-(1H-pyrazol-4-yl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid tert-butyl-methyl-amide (1)

To a solution of8-bromo-N-(tert-butyl)-7-methoxy-N-methyl-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(1 g, 0.0021 mol) in dioxane (20 mL) was added4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (611 mg,0.0031 mol), PdCl₂(dppf)CH₂Cl₂ (86 mg, 0.0001 mol) and cesium fluoride(800 mg, 0.0053 mol) at RT under nitrogen. The reaction mixture wasdegassed with nitrogen for 20 min and water (4 mL) was added at RT. Thereaction mixture was stirred at 100° C. for 12 h. The reaction mixturewas filtered through celite and washed with DCM (20 mL). The filtratewas concentrated under vacuum; the crude product was dissolved in DCM(200 mL), washed with water (10 ml), brine (10 mL) and dried over sodiumsulphate. The organic solvent was removed under vacuum; the crudeproduct was purified by column chromatograph using pet ether: ethylacetate as eluent to afford the desired compound (0.5 g, 51%) as anoff-white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 8.02-8.01 (dd, J=1.4, 3.2 Hz, 1H), 7.89-7.87(dd, J=3.2, 5.1 Hz, 1H), 7.54 (bs, 2H), 7.37-7.36 (dd, J=1.4, 5.1 Hz,1H), 6.85 (s, 1H), 6.74 (s, 1H), 5.35 (s, 2H), 3.83 (s, 3H), 3.16 (s,3H), 1.42 (s, 9H). m/z: 464 [M+H]⁺

Example 27-Methoxy-8-pyridin-3-yl-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid tert-butyl-methyl-amide (2)

To a solution of8-bromo-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid tert-butyl-methyl-amide (Example 1 step 10) (100 mg, 0.2 mmol) inDME (10 mL) was added pyridine-3-boronic acid (52 mg, 0.4 mmol), tetrakis (triphenylphospine)palladium (13 mg, 0.01 mmol) and potassiumcarbonate (90 mg, 0.6 mmol) at RT under nitrogen. The reaction mixturewas degassed with nitrogen for 10 min and water was added (1 mL). Thereaction mixture was stirred at 90° C. for 16 h. The reaction mixturewas filtered through celite. Filtrate was concentrated under vacuum; thecrude product was dissolved in DCM (200 mL), washed with water (10 ml),brine (10 mL) and dried over sodium sulphate. The solvent was removedunder vacuum to provide the crude product. The crude product was slurredwith diethyl ether (5 mL), filtered and dried to afford the desiredcompound (95 mg, 98%) as an off white solid.

¹H NMR (400 MHz, CDCl₃) δ 8.50-8.47 (m, 2H), 7.67-7.64 (m, 1H),7.53-7.52 (dd, J=1.2, 3.2 Hz, 1H), 7.49-7.47 (dd, J=3.2, 5.2 Hz, 1H),7.27-7.22 (m, 2H), 6.77 (s, 1H), 6.69 (s, 1H), 5.52 (s, 2H), 3.82 (s,3H), 3.28 (s, 3H), 1.52 (s, 9H). m/z: 475 [M+H]⁺

Example 3(4-Cyclobutanecarbonyl-[1,4]diazepan-1-yl)-(7-methoxy-8-pyridin-3-yl-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazol-3-yl)-methanone(3) Step 1:(8-Bromo-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazol-3-yl)-(4-cyclobutanecarbonyl-[1,4]diazepan-1-yl)-methanone

To a solution of8-bromo-7-methoxy-1-(3-thienyl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylicacid (example 1 step 9) (0.5 g, 0.001 mol) in DCM (10 mL) was added1-(cyclobutyl carbonyl)-1,4 diazepane (0.25 g, 0.001 mol), T₃P (1 mL,0.001 mol, 50% soln in EtOAc) and TEA (0.2 mL, 0.003 mol) at RT undernitrogen. The reaction mixture was stirred at RT for 16 h. The reactionmixture was quenched with saturated sodium bicarbonate (10 mL),extracted with DCM (2×25 mL). The combined organic layer was washed withNaHCO₃ solution (1×100 mL, 100%), brine (100 mL) and dried overanhydrous sodium sulphate. The solvent was removed under vacuum, thecrude product was purified by column chromatography using pet ether andethyl acetate (9:1) as eluent to afford the desired compound as (0.4 g,57%) an off white solid.

¹H NMR (400 MHz, CDCl₃) δ 7.51-7.48 (m, 2H), 7.22-7.20 (m, 1H), 6.99 (t,J=4.0 Hz, 1H), 6.60 (t, J=2.4 Hz, 1H), 5.54-5.51 (dd, J=4.0, 12.0 Hz,2H), 4.18-4.17 (m, 2H), 3.86 (s, 3H), 3.81-3.79 (m, 3H), 3.71-3.60 (m,3H), 3.57-3.54 (m, 1H), 2.36-2.34 (m, 2H), 1.99-1.95 (m, 2H), 1.94-1.90(m, 4H). m/z: 571 [M+H]⁺

Step 2:(4-Cyclobutanecarbonyl-[1,4]diazepan-1-yl)-(7-methoxy-8-pyridin-3-yl-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazol-3-yl)-methanone

To a solution of(4-cyclobutanecarbonyl-[1,4]diazepan-1-yl)-(7-methoxy-8-pyridin-3-yl-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazol-3-yl)-methanone(250 mg, 0.4 mmol) in DME (10 mL) was added pyridine-3-boronic acid (100mg, 0.8 mmol), tetra kis (triphenylphospine)palladium (30 mg, 0.02 mmol)and potassium carbonate (150 mg, 0.001 mol) at RT under nitrogen. Thereaction mixture was degassed with nitrogen for 10 min and water (2 mL)was added. The reaction mixture was stirred at 90° C. for 16 h. Thereaction mixture was filtered through celite and washed with DCM (20mL). Filtrate was concentrated under vacuum; crude product was dissolvedin DCM (200 mL), washed with water (10 ml), brine (10 mL) and dried oversodium sulphate. The solvent was removed under vacuum; crude product wasslurred with diethyl ether (10 mL), filtered and dried to afford thedesired compound as (240 mg, 96%) an off white solid.

¹H NMR (400 MHz, CDCl₃) δ 8.49-8.47 (dd, J=1.6, 4.8 Hz, 2H), 7.67 (t,J=2.0 Hz, 1H), 7.52-7.47 (m, 2H), 7.27-7.24 (m, 2H), 6.83-6.80 (dd,J=1.6, 4.8 Hz, 1H), 6.68 (t, J=4.0, Hz, 1H), 5.59-5.56 (dd, J=1.6, 10.4Hz, 2H), 4.18-4.17 (m, 2H), 3.86 (s, 4H), 3.81-3.79 (m, 1H), 3.71-3.60(m, 2H), 3.57-3.54 (m, 1H), 3.36-3.34 (m, 1H), 2.36-2.349 m, 2H),2.12-1.99 (m, 6H), 0.98-0.97 (m, 1H). m/z: 570 [M+H]

Example 48-Isobutyl-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid tert-butyl-methyl-amide (5) Step 1:7-Methoxy-8-(2-methyl-propenyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid ethyl ester

To a solution of ethyl8-bromo-7-methoxy-1-(3-thienyl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate(example 1 step 8) (1 g, 0.002 mol) in THF (20 mL) was added2,4,6-Tris-(2-methyl-propenyl)-cyclotriboroxanepyridine complex (380 mg,0.001 mol), bis (triphenylphospine)palladium (II) dichloride (80 mg, 0.1mmol) and potassium tri phosphate (63 mg, 0.004 mol) at RT undernitrogen. The reaction mixture was degassed with nitrogen for 10 min andwater (2 mL) was added at RT. The reaction mixture was stirred at 70° C.for 4 h. The reaction mixture was filtered through celite and washedwith DCM (50 mL). The filtrate was concentrated under vacuum; crudeproduct was dissolved in DCM (200 mL), washed with water (20 ml), brine(20 mL) and dried over sodium sulphate. The organic solvent was removedunder vacuum; crude product was purified by column chromatograph withpet ether: ethyl acetate as eluent to afford the desired product as (0.9g, 96%) a light yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ 8.00 (m, 1H), 7.83-7.82 (d, J=3.2 Hz, 1H),7.33-7.32 (dd, J=1.6, 5.2 Hz, 1H), 6.65 (s, 1H), 6.56 (s, 1H), 6.00 (s,1H), 5.56 (s, 2H), 4.32-4.26 (m, 2H), 3.78 (s, 3H), 1.76 (s, 3H), 4.52(s, 3H), 1.23-1.18 (m, 3H). m/z: 411.5 [M+H]⁺

Step 2:8-Isobutyl-7-methoxy-1-(3-thienyl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate

To a solution of ethyl7-methoxy-8-(2-methylprop-1-en-1-yl)-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate(step 1) (1 g, 0.02 mol) in methanol and ethyl acetate mixture (40 mL)was added palladium on carbon (10%, 0.5 g). The reaction mixture washydrogenated under 3 bar of pressure hydrogen for 4 h at RT. Thereaction mixture was filtered through a celite bed and filtrate wasconcentrated under vacuum. The residue was purified by columnchromatography using pet ether: ethyl acetate as eluent to afford thetitle compound (0.7 g, 70%) as an off white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 7.97-7.96 (dd, J=1.2, 3.2 Hz, 1H), 7.83-7.82(dd, J=3.2, 5.2 Hz, 1H), 7.31-7.30 (dd, J=1.2, 5.2 Hz, 1H), 6.64 (s,1H), 6.37 (s, 1H), 5.43 (s, 2H), 4.32-4.27 (m, 2H), 3.75 (s, 3H),2.12-2.10 (m, 2H), 1.62-1.55 (m, 1H), 1.31-1.22 (m, 3H), 0.85-0.83 (d,J=4.0 Hz, 6H). m/z: 413 [M+H]⁺

Step 3:8-Isobutyl-7-methoxy-1-(3-thienyl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylicacid

To a solution of ethyl8-isobutyl-7-methoxy-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate(250 mg, 0.006 mol) in mixture of THF (21 mL), H₂O (6 mL), MeOH (3 mL)was added LiOH (0.08 g, 0.001 mol) at RT. The reaction mixture wasstirred at RT for 2 h. The reaction mixture was evaporated and acidifiedwith 1.5N HCl solution. The solid was filtered and dried under highvacuum to afford the desired compound (200 mg, 87%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 13.02 (bs, 1H), 7.96-7.95 (dd, J=1.6, 3.2Hz, 1H), 7.83-7.81 (dd, J=3.2, 5.2 Hz, 1H), 7.31-7.29 (dd, J=1.2, 5.2Hz, 1H), 6.64 (s, 1H), 6.37 (s, 1H), 5.42 (s, 2H), 3.73 (s, 3H),2.12-2.11 (m, 2H), 1.62-1.55 (m, 1H), 0.72-0.711 (d, J=4.0 Hz, 6H). m/z:385 [M+H]⁺

Step 4:8-Isobutyl-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid tert-butyl-methyl-amide (5)

To a solution of8-isobutyl-7-methoxy-1-(3-thienyl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylicacid (step 3) (180 mg, 0.4 mmol) in DCM (20 mL) was added N-tert-butylmethyl amine (50 mg, 0.5 mmol), HATU (0.22 g, 5 mmol) and diisopropylethyl amine (0.2 mL, 0.7 mmol) at RT under nitrogen. The reactionmixture was stirred at RT for 16 h. The reaction mixture was quenchedwith sodium bicarbonate (10 mL, 10%), extracted with DCM (2×25 mL). Thecombined organic layer was washed with NaHCO₃ solution (1×100 mL, 10%),brine (100 mL) and dried over anhydrous sodium sulphate. The solvent wasremoved under vacuum; the crude product was purified by columnchromatography using pet ether and ethyl acetate (9:1) as eluent toafford the desired compound (140 mg, 66%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 7.91-7.90 (dd, J=1.6, 3.2 Hz, 1H), 7.80-7.85(dd, J=3.2, 5.2 Hz, 1H), 7.29-7.28 (dd, J=1.2, 5.2 Hz, 1H), 6.64 (s,1H), 6.40 (s, 1H), 5.29 (s, 2H), 3.73 (s, 3H), 3.14 (s, 3H), 2.13-2.11(m, 2H), 1.63-1.55 (m, 1H), 1.41 (s, 9H), 0.72-0.711 (d, J=4.0 Hz, 6H).m/z: 454 [M+H]⁺

Example 57-Methoxy-8-(2-methyl-propenyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid tert-butyl-methyl-amide (6) Step 1:8-Bromo-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid tert-butyl-methyl-amide (4)

To a solution of8-bromo-7-methoxy-1-(3-thienyl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylicacid (example 1 step 9) (150.00 mg; 0.37 mmol; 1.00 eq.) in DCM (0.50ml; 7.80 mmol; 21.18 eq.) was added N,N-Diisopropylamine (0.12 ml; 0.74mmol; 2.00 eq.), o-(benzotriazol-1-yl)-n,n,n′,n′-tetramethyluroniumtetrafluoroborate (TBTU) (236.53 mg; 0.74 mmol; 2.00 eq.), andn-tert-butyl-methylamine (48.16 mg, 0.55 mmol, 1.5 eq.). The reactionwas stirred at RT for 2 h. The crude product was purified by columnchromatography (Biotage) using EtOAc/Hex as eluent to afford the desiredcompound (120 mg, 68%) as a white solid.

Step 2:7-Methoxy-8-(2-methyl-propenyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid tert-butyl-methyl-amide (6)

To8-bromo-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid tert-butyl-methyl-amide (50.00 mg; 0.10 mmol; 1.00 eq.) (example 5step 1) in a microwave vial, was added2,4,6-Tris-(2-methyl-propenyl)-cyclotriboroxane pyridine (51.14 mg; 0.16mmol; 1.50 eq.),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(ii), complexwith dichloromethane (1:1) (8.57 mg; 0.01 mmol; 0.10 eq.), dioxane (1.00ml; 11.74 mmol; 111.82 eq.) and cesium carbonate (0.16 ml; 0.31 mmol;3.00 eq., 3M). The vessel was sealed, vacuumed and backfilled withnitrogen (3 times). Reaction was microwaved at 120° C. for 2 h. Thecrude product was purified by column chromatography (Biotage) usingEtOAc/Hex as eluent to afford the desired compound (6.6 mg, 14%) as awhite solid.

¹H NMR (400 MHz, MeOD) δ 7.75 (dd, J=3.2, 1.4 Hz, 1H), 7.69 (dd, J=5.1,3.2 Hz, 1H), 7.27 (dd, J=5.1, 1.4 Hz, 1H), 6.70 (s, 1H), 6.63 (s, 1H),6.07 (s, 1H), 5.33 (s, 2H), 3.80 (s, 3H), 3.20 (s, 3H), 1.80 (d, J=1.3Hz, 3H), 1.54 (s, 9H), 1.50 (d, J=1.2 Hz, 3H). m/z: 452 [M+H]⁺

Example 67-Methoxy-8-(2-methyl-propenyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid (2-acetylamino-ethyl)-amide (7) Step 1: Ethyl7-methoxy-8-(2-methylprop-1-en-1-yl)-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate

To a solution of ethyl8-bromo-7-methoxy-1-(3-thienyl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate(6 g, 0.0138 mol) in THF (100 mL) was added2,4,6-Tris-(2-methyl-propenyl)-cyclotriboroxanepyridine complex (5.8 g,0.018 mol), bis(triphenylphospine)palladium (II) dichloride (1.0 g, 1.38mmol) and potassium triphosphate (3.8 g, 0.0276 mol) at RT undernitrogen. The reaction mixture was degassed with nitrogen for 10 min andwater (10 mL) was added at RT. The reaction mixture was stirred at 80°C. for 8 h. The reaction mixture was filtered through celite and washedwith DCM (50 mL). The filtrate was concentrated under vacuum; crudeproduct was dissolved in DCM (200 mL), washed with water (20 ml), brine(20 mL) and dried over sodium sulphate. The organic solvent was removedunder vacuum; crude product was purified by column chromatograph usingpet ether: ethyl acetate as eluent to afford the desired compound as(5.5 g, 98%) a pale yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ 8.00 (m, 1H), 7.83-7.82 (d, J=3.2 Hz, 1H),7.33-7.32 (dd, J=1.6, 5.2 Hz, 1H), 6.65 (s, 1H), 6.56 (s, 1H), 6.00 (s,1H), 5.56 (s, 2H), 4.32-4.26 (m, 2H), 3.78 (s, 3H), 1.76 (s, 3H), 4.52(s, 3H), 1.23-1.18 (m, 3H). m/z: 411.5 [M+H]⁺

Step 2:7-Methoxy-8-(2-methyl-propenyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid

To a solution of ethyl7-methoxy-8-(2-methylprop-1-en-1-yl)-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate(7 g, 0.0171 mol) in mixture of THF (70 mL), H₂O (20 mL), MeOH (10 mL)was added LiOH.H₂O (2.1 g, 0.0512 mol) at RT. The reaction mixture wasstirred at RT for 4 h. The reaction mixture was evaporated and acidifiedwith 1.5N HCl solution. The solid was filtered and dried under highvacuum to afford the desired compound (5.5 g, 85%) as an off-whitesolid.

¹H NMR (400 MHz, DMSO-d₆) δ 13.02 (bs, 1H), 7.96-7.95 (dd, J=1.6, 3.2Hz, 1H), 7.83-7.81 (dd, J=3.2, 5.2 Hz, 1H), 7.31-7.29 (dd, J=1.2, 5.2Hz, 1H), 6.64 (s, 1H), 6.37 (s, 1H), 5.42 (s, 2H), 3.73 (s, 3H),2.12-2.11 (m, 2H), 1.62-1.55 (m, 1H), 0.72-0.711 (d, J=4.0 Hz, 6H). m/z:383 [M+H]⁺

Step 3:7-Methoxy-8-(2-methyl-propenyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid (2-acetylamino-ethyl)-amide (7)

To7-methoxy-8-(2-methyl-propenyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid (30 mg 0.08 mmol) in DCM (1.00 ml; 15.60 mmol; 198.87 eq.) wasadded N,N-Diisopropylethylamine (0.02 ml; 0.09 mmol; 1.20 eq.),N-acetylethylenediamine (9.61 mg, 0.09 mmol, 1.2 eq.) and T3P (0.03 ml;0.12 mmol; 1.50 eq.). The reaction was stirred at RT for 1.5 h. Thecrude product was purified by column chromatography using EtOAc/Hex aseluent to afford the desired compound (27.4 mg, 73%) as a white solid.

¹H NMR (500 MHz, CD₃OD) δ 7.74 (dd, J=3.1, 1.2 Hz, 1H), 7.67 (dd, J=5.0,3.2 Hz, 1H), 7.26 (dd, J=5.1, 1.1 Hz, 1H), 6.66 (s, 1H), 6.58 (s, 1H),6.04 (s, 1H), 5.48 (s, 2H), 3.76 (s, 3H), 3.46 (t, J=6.0 Hz, 2H),3.41-3.33 (m, 2H), 1.94 (s, 3H), 1.78 (s, 3H), 1.48 (s, 3H). m/z: 467[M+H]⁺

The following compounds were prepared using procedures analogous tothose disclosed in Example 6.

Product Amine LC/MS NMR

m/z: 492 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.59-7.56 (m, 1H), 7.54 (dd,J = 5.0, 3.3 Hz, 1H), 7.40-7.34 (m, 1H), 7.26 (dd, J = 5.1, 1.4 Hz, 1H),6.71 (s, 1H), 6.60 (s, 1H), 6.12 (s, 1H), 5.63 (s, 2H), 3.84 (s, 3H),3.49 (dd, J = 12.3, 6.5 Hz, 2H), 3.15-3.09 (m, 2H), 1.98 (dtd, J = 8.5,6.0, 2.6 Hz, 2H), 1.85 (d, J = 1.2 Hz, 3H), 1.52 (d, J = 1.1 Hz, 3H).

m/z: 481 [M + H]⁺ ¹H NMR (400 MHz, MeOD) δ 7.74 (dd, J = 3.2, 1.4 Hz,1H), 7.67 (dd, J = 5.1, 3.2 Hz, 1H), 7.26 (dd, J = 5.1, 1.4 Hz, 1H),6.66 (s, 1H), 6.58 (s, 1H), 6.05 (d, J = 0.6 Hz, 1H), 5.49 (s, 2H), 3.78(s, 3H), 3.39 (dd, J = 10.1, 3.4 Hz, 2H), 3.26 (t, J = 6.7 Hz, 2H), 1.95(s, 3H), 1.82-1.73 (m, 5H), 1.48 (d, J = 1.2 Hz, 3H).

m/z: 495 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.55 (dd, J = 3.1, 1.3 Hz,1H), 7.50 (dd, J = 5.1, 3.2 Hz, 1H), 7.24 (dd, J = 5.1, 1.4 Hz, 1H),7.11 (s, 1H), 6.71 (s, 1H), 6.57 (s, 1H), 6.12 (s, 1H), 5.60 (s, 2H),4.39-4.31 (m, 2H), 3.82 (s, 3H), 3.72 (dd, J = 8.7, 7.2 Hz, 2H), 3.66(dd, J = 12.3, 6.0 Hz, 2H), 3.52 (t, J = 6.1 Hz, 2H), 1.85 (d, J = 1.3Hz, 3H), 1.52 (d, J = 1.2 Hz, 3H).

m/z: 509 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.54 (dd, J =3.2, 1.4 Hz,1H), 7.49 (dd, J = 5.1, 3.2 Hz, 1H), 7.24 (dd, J = 5.1, 1.4 Hz, 1H),7.19 (s, 1H), 6.71 (s, 1H), 6.57 (s, 1H), 6.11 (s, 1H), 5.61 (s, 2H),4.38-4.30 (m, 2H), 3.81 (s, 3H), 3.65-3.58 (m, 2H), 3.48 (q, J = 6.7 Hz,2H), 3.39 (t, J = 6.8 Hz, 2H), 1.89 (dd, J = 13.7, 6.8 Hz, 2H), 1.84 (d,J = 1.2 Hz, 3H), 1.52 (d, J = 1.2 Hz, 3H).

m/z: 454 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.55 (dd, J = 3.2, 1.4 Hz,1H), 7.51 (dd, J = 5.1, 3.2 Hz, 1H), 7.24 (dd, J = 5.1, 1.4 Hz, 1H),6.95 (s, 1H), 6.68 (s, 1H), 6.57 (s, 1H), 6.11 (s, 1H), 5.59 (s, 2H),3.82 (s, 3H), 3.72 (s, 2H), 1.85 (d, J = 1.3 Hz, 3H), 1.52 (d, J = 1.2Hz, 3H), 1.41 (s, 6H).

m/z: 522 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.52 (dd, J = 3.2, 1.4 Hz,1H), 7.48 (dd, J = 5.1, 3.2 Hz, 1H), 7.24 (dd, J = 5.1, 1.4 Hz, 1H),6.74 (s, 1H), 6.58 (s, 1H), 6.12 (s, 1H), 5.52 (s, 2H), 5.00 (d, J =13.1 Hz, 1H), 4.55 (d, J = 13.4 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H), 3.83(s, 3H), 3.47-3.36 (m, 1H), 3.09-2.96 (m, 1H), 2.66-2.54 (m, 1H),2.08-1.92 (m, 2H), 1.85 (d, J = 1.3 Hz, 3H), 1.81 (d, J = 11.8 Hz, 2H),1.54 (d, J = 1.2 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H).

m/z: 564 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.55 (ddd, J = 4.6, 3.2, 1.4Hz, 2H), 7.51 (dd, J = 5.1, 3.2 Hz, 1H), 7.25 (td, J = 4.7, 1.4 Hz, 1H),6.69 (s, 1H), 6.57 (s, 1H), 6.11 (s, 1H), 5.63 (s, 2H), 4.33 (s, 1H),3.98 (dd, J = 8.2, 4.0 Hz, 2H), 3.83 (d, J = 3.7 Hz, 3H), 2.28-2.4 (m,1H), 2.56 (s, 1H), 2.42-2.26 (m, 2H), 2.05 (d, J = 13.2 Hz, 1H), 1.92(dd, J = 21.8, 15.1 Hz, 2H), 1.85 (s, 3H), 1.52 (s, 3H), 1.48-1.42 (m,9H).

m/z: 494 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.52 (dd, J = 3.2, 1.4 Hz,1H), 7.48 (dd, J = 5.1, 3.3 Hz, 1H), 7.24 (dd, J = 5.1, 1.4 Hz, 1H),6.73 (s, 1H), 6.58 (s, 1H), 6.12 (s, 1H), 5.52 (s, 2H), 5.12-5.03 (m,2H), 4.62-4.52 (m, 2H), 3.82 (s, 3H), 3.11-3.00 (m, 2H), 3.42-3.48 (m,2H), 2.81- 2.68 (m, 1H), 1.85 (d, J = 1.2 Hz, 3H), 1.53 (d, J = 1.2 Hz,3H).

m/z: 522 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.51-7.49 (m, 1H), 7.47 (dd,J = 5.1, 3.3 Hz, 1H), 7.25-7.22 (m, 1H), 6.76 (d, J = 3.4 Hz, 1H), 6.58(s, 1H), 6.12 (s, 1H), 5.55 (d, J = 3.4 Hz, 2H), 4.40-4.23 (m, 2H),4.11-4.00 (m, 2H), 3.86 (d, J = 5.2 Hz, 1H), 3.82 (s, 3H), 3.79-3.74 (m,1H), 3.69 (d, J = 5.9 Hz, 3H), 2.62-2.54 (m, 2H), 2.30-2.20 (m, 1H),2.04-1.94 (m, 1H), 1.85 (d, J = 1.2 Hz, 2H), 1.81-1.73 (m, 3H), 1.55 (s,3H).

m/z: 508 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.52-7.47 (m, 1H), 7.46 (d,J = 4.7 Hz, 1H), 7.23 (d, J = 3.7 Hz, 1H), 6.75 (d, J = 4.3 Hz, 1H),6.57 (s, 1H), 6.12 (s, 1H), 5.53 (d, J = 6.1 Hz, 2H), 4.35-4.21 (m, 1H),4.04 (dd, J = 17.7, 16.6 Hz, 1H), 3.91-3.73 (m, 5H), 3.51 (s, 1H),2.68-2.52 (m, 1H), 2.30-2.18 (m, 1H), 2.13-1.94 (m, 3H), 1.85 (s, 3H),1.82-1.72 (m, 1H), 1.54 (s, 3H).

m/z: 579 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.52-7.48 (m, 1H), 7.46 (dd,J = 5.1, 3.3 Hz, 1H), 7.26-7.21 (m, 1H), 6.76 (d, J = 7.6 Hz, 1H), 6.57(s, 1H), 6.12 (s, 1H), 5.53 (s, 2H), 4.63-4.51 (m, 1H), 4.51- 4.39 (m,1H), 4.27-4.18 (m, 1H), 4.05-3.91 (m, 1H), 3.82 (s, 3H), 3.75-3.51 (m,2H), 2.22-2.11 (m, 1H), 2.03-1.90 (m, 2H), 1.85 (s, 3H), 1.82-1.68 (m,2H), 1.54 (d, J = 1.2 Hz, 3H), 1.45 (d, J = 8.1 Hz, 9H).

m/z: 479 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.51 (d, J = 10.5 Hz, 1H),7.47-7.41 (m, 1H), 7.23 (d, J = 5.0 Hz, 1H), 6.76 (s, 1H), 6.57 (s, 1H),6.12 (s, 1H), 5.53 (s, 2H), 4.35-4.16 (m, 2H), 4.02-3.85 (m, 3H), 3.82(s, 2H), 3.64-3.50 (m, 2H), 3.29-3.19 (m, 2H), 2.34-2.23 (m, 1H), 2.10-1.97 (m, 2H), 1.85 (s, 3H), 1.54 (s, 3H).

m/z: 480 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.51 (dd, J = 3.2, 1.4 Hz,1H), 7.47 (dd, J = 5.1, 3.3 Hz, 1H), 7.22 (dd, J = 5.1, 1.3 Hz, 1H),6.72 (s, 1H), 6.58 (s, 1H), 6.12 (s, 1H), 5.47 (s, 2H), 4.10-4.06 (m,2H), 3.88-3.84 (m, 2H), 3.82 (s, 3H), 3.50 (s, 2H), 1.85 (d, J = 1.0 Hz,3H), 1.55 (s, 6H), 1.53 (d, J = 0.9 Hz, 3H).

m/z: 468 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.53 (d, J = 2.2 Hz, 1H),7.48 (dd, J = 5.0, 3.3 Hz, 1H), 7.23 (d, J = 5.1 Hz, 1H), 6.72 (s, 1H),6.58 (s, 1H), 6.12 (s, 1H), 5.44 (s, 2H), 5.07 (t, J = 6.3 Hz, 1H), 3.83(s, 3H), 3.80 (d, J = 6.2 Hz, 2H), 3.32 (s, 3H), 1.85 (s, 3H), 1.52 (s,3H), 1.46 (s, 6H).

m/z: 464 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.51-7.44 (m, 2H), 7.22 (d,J = 4.8 Hz, 1H), 6.73 (s, 1H), 6.58 (s, 1H), 6.12 (s, 1H), 5.64 (s, 2H),5.62 (d, J = 6.7 Hz, 2H), 4.69 (d, J = 6.8 Hz, 2H), 4.51-4.43 (m, 2H),3.82 (s, 3H), 2.63-2.55 (m, 2H), 1.85 (s, 3H), 1.54 (s, 3H).

m/z: 547 [M + H]⁺

m/z: 547 [M + H]⁺

m/z: 480 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.57-7.44 (m, 2H), 7.23 (d,J = 5.0 Hz, 1H), 6.72 (s, 1H), 6.58 (s, 1H), 6.12 (s, 1H), 5.83 (s, 1H),5.54 (s, 2H), 4.47-4.37 (m, 1H), 3.99-3.88 (m, 1H), 3.82 (s, 3H), 3.68(d, J = 11.9 Hz, 1H), 2.04-1.87 (m, 3H), 1.85 (s, 3H), 1.82-1.74 (m,2H), 1.54 (d, J = 4.6 Hz, 6H).

m/z: 452 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.52 (dd, J = 3.2, 1.4 Hz,1H), 7.48 (dd, J = 5.1, 3.3 Hz, 1H), 7.23 (dd, J = 5.1, 1.4 Hz, 1H),6.72 (s, 1H), 6.58 (s, 1H), 6.12 (s, 1H), 5.55 (s, 2H), 4.32 (t, J = 7.0Hz, 2H), 3.83 (s, 3H), 3.82- 3.71 (m, 6H), 1.85 (d, J = 1.0 Hz, 3H),1.53 (d, J = 0.9 Hz, 3H).

m/z: 452 [M + H]⁺ ¹H NMR (500 MHz, cdcl₃) δ 7.49 (dd, J = 3.1, 1.5 Hz,1H), 7.48-7.42 (m, 1H), 7.22 (dd, J = 6.5, 2.8 Hz, 1H), 6.71 (d, J = 6.3Hz, 1H), 6.54 (s, 1H), 6.10 (s, 1H), 5.65-5.54 (m, 1H), 4.57- 4.50 (m,1H), 4.16 (t, J = 12.8 Hz, 1H), 4.13-4.04 (m, 2H), 3.85-3.81 (m, 1H),3.80 (s, 3H), 3.75 (d, J = 2.7 Hz, 1H), 2.10-1.94 (m, 2H), 1.83 (s, 3H),1.52 (s, 3H).

The following compounds were prepared using procedures analogous tothose disclosed in example 4:

Compound Starting material LC/MS NMR

m/z = 482 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 7.94 (s, 1H), 7.84-7.79 (m, 1H),7.31 (d, 1H), 6.66 (s, 1H), 6.41 (s, 1H), 5.34 (s, 2H), 3.94 (t, 2H),3.78- 3.70 (m, 5H), 3.42 (s, 2H), 2.14 (d, 2H), 1.62 (septet, 1H), 1.42(s, 6H), 0.74 (d, J = 6.5 Hz, 6H).

m/z = 470 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 8.67 (s, 1H), 7.99 (dd, 1H), 7.84(dd, 1H), 7.34 (dd, 1H), 6.66 (s, 1H), 6.38 (s, 1H), 5.45 (s, 2H), 5.14(s, 1H), 4.68 (d, 2H), 4.51 (d, 2H), 3.76 (s, 3H), 3.68 (s, 2H), 2.14(d, 2H), 1.61 (septet, 1H), 0.74 (d, 6H).

m/z = 454 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 8.87 (s, 1H), 8.00 (dd, 1H), 7.84(dd, 1H), 7.35 (dd, 1H), 6.66 (s, 1H), 6.38 (s, 1H), 5.46 (s, 2H), 4.70(d, 2H), 4.31 (d, 2H), 3.75 (s, 3H), 2.14 (d, 2H), 1.66- 1.54 (m, 4H),0.73 (d, 6H).

Example 78-Isopropoxy-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid tert-butyl-methyl-amide (19) Step 1:3-Chloro-1-(2-hydroxy-4,5-dimethoxyphenyl)propan-1-one

To a stirred suspension of 3, 4-dimethoxy phenol (10 g, 0.06 mol) andchloropropanoyl chloride (12.5 g, 0.12 mol) was added borontrifluorideethylethrate (8.8 mL, 0.06 mol) in drops at 60° C. undernitrogen atmosphere. After the complete addition, the reaction mixturewas heated to 70° C. for 1 h. The reaction mixture was cooled to RT andquenched with ice-water (200 mL) and extracted with DCM (500 mL). Theaqueous layer was re-extracted (2×100 mL) DCM, the combined organiclayer was dried over sodium sulphate and concentrated under vacuum. Thecrude mass was purified by column chromatography using pet ether/ethylacetate (8:2) as eluent to afford the desired compound (12 g, 76%) as alight yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ 12.2 (bs, 1H), 7.27 (s, 1H), 6.55 (s, 1H),4.12-4.10 (m, 2H), 3.79 (s, 3H), 3.71 (s, 3H), 2.48-2.43 (m, 2H).

Step 2: 6,7-Dimethoxy-2,3-dihydro-4H-chromen-4-one

To a stirred solution of3-Chloro-1-(2-hydroxy-4,5-dimethoxyphenyl)propan-1-one (13 g, 0.05 mol)in ethanol was added dry K₂CO₃ (16.3 g, 0.10 mol) in lots at RT undernitrogen. The resulting suspension was stirred at RT for 16 h. Thereaction mixture was filtered and concentrated under vacuum. The crudemass was dissolved in ethyl acetate (200 mL), washed with 5% sodiumbicarbonate (50 mL), brine (50 mL) and dried over sodium sulphate. Theorganic solvent was concentrated; the residue was purified by columnchromatography using pet ether/ethyl acetate (8:2) as eluent to affordthe desired compound (9 g, 81%) as a light brown solid.

¹H NMR (400 MHz, DMSO-d₆) δ 7.12 (s, 1H), 6.59 (s, 1H), 4.47-4.44 (m,2H), 3.80 (s, 3H), 3.72 (s, 3H), 2.69-2.65 (m, 2H).

Step 3: 6,7-Dihydroxy-2,3-dihydro-4H-chromen-4-one

The mixture of 6,7-dimethoxy-2,3-dihydro-4H-chromen-4-one (2.5 g, 0.01mol) and pyridine hydrochloride (20 g, 0.20 mol) was heated at 170° C.under nitrogen for 12 h. The reaction mixture was slurred with DCM (100mL), the separated solid was filtered and filtrate was concentratedunder vacuum. The crude product was purified by column chromatographyusing pet ether/ethyl acetate (5:5) as eluent to afford the desiredcompound (1 g, 50%) as a light white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 9.72 (bs, 2H), 7.04 (s, 1H), 6.30 (s, 1H),4.37-4.34 (m, 2H), 2.60-2.57 (m, 2H).

Step 4: 6-Hydroxy-7-methoxy-2,3-dihydro-4H-chromen-4-one

To a stirred solution of 6,7-dihydroxy-2,3-dihydro-4H-chromen-4-one (5.5g, 0.0305 mol) in DMF (60 mL) was added dry K₂CO₃ (4.2 g, 0.0305 mol) atRT under nitrogen. The reaction mixture was stirred at RT for 15 min andthen added methyl iodide (1.3 mL, 0.0214 mol) in drops at RT. Thereaction mixture was stirred at RT for 2 h. The reaction mixture wasfiltered and filtrate was concentrated under vacuum. The crude productwas purified by column chromatography using pet ether/ethyl acetate(9:1) as eluent to afford the desired compound (4 g, 68%) as a lightbrown solid.

¹H NMR (400 MHz, DMSO-d₆) δ 9.05 (bs, 1H), 7.05 (s, 1H), 6.53 (s, 1H),4.43-4.40 (m, 2H), 3.80 (s, 3H), 2.64-2.61 (m, 2H).

Step 5: 6-Isopropoxy-7-methoxy-2,3-dihydro-4H-chromen-4-one

To a stirred solution of6-hydroxy-7-methoxy-2,3-dihydro-4H-chromen-4-one (4.0 g, 0.0206 mol) inDMF (80 mL) was added dry K₂CO₃ (5.7 g, 0.0412 mol) at RT undernitrogen. The reaction mixture was stirred at RT for 15 min and thenadded 2-lodo propane (6.2 mL, 0.0618 mol) in drops at RT. The reactionmixture was stirred at 65° C. for 8 h. The reaction mixture was filteredand filtrate was concentrated under vacuum. The crude product wasdissolved in ethyl acetate (2×200 mL), washed with water (50 mL), brine(50 mL) and dried over sodium sulphate. The organic solvent wasconcentrated, crude mass was purified by column chromatography using petether/ethyl acetate (8:2) as eluent to afford the desired compound (4.1g, 87%) as a light brown solid.

¹H NMR (400 MHz, DMSO-d₆) δ 7.13 (s, 1H), 6.59 (s, 1H), 4.48-4.40 (m,3H), 3.80 (s, 3H), 2.68-2.65 (m, 2H), 1.21 (s, 3H), 1.20 (s, 3H).

Step 6: Ethyl(2Z)-hydroxy(6-isopropoxy-7-methoxy-4-oxo-2H-chromen-3(4H)-ylidene)acetate

Diisopropyl amine (6.9 mL, 0.0495 mol) was taken in dry THF (150 mL) atRT under nitrogen atmosphere. The reaction mixture was cooled to −78° C.and n-Butyl lithium (1.6 M solution in hexane, 28.6 mL, 0.0457 mol) wasadded in drops over a period of 30 min. After the addition, the reactionmixture stirred at same temperature for 15 min and then slowly warmed to−10° C. and stirred further for 30 min. Reaction mixture was againre-cooled to −78° C.,6-Isopropoxy-7-methoxy-2,3-dihydro-4H-chromen-4-one (9 g, 0.0381 mol) inTHF (50 mL) was added in drops over period of 30 min and stirred at −78°C. After 1 h, diethyl oxalate (7.8 mL, 0.0571 mol) was added in drops at−78° C.; the reaction mixture was slowly brought to 0° C. and stirredfor 1 h. The reaction mixture was cooled to −5° C., quenched with asolution of 1.5N HCl and extracted with ethyl acetate (100 mL×2). Thecombined organic layer was washed with water (100 mL), brine (50 mL),dried over sodium sulphate and concentrated to afford the desiredcompound (10.5 g, 92%) as a pale yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ. 7.17-7.13 (d, J=16 Hz, 1H), 6.61-6.59 (d,J=24 Hz, 1H), 5.16-5.12 (m, 1H), 4.47-4.24 (m, 1H), 4.21 (s, 3H), 2.97(s, 3H), 2.54-5.53 (m, 1H), 1.21 (s, 6H).

Step 7:8-Isopropoxy-7-methoxy-1-(3-thienyl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate

To a solution of (ethyl(2Z)-hydroxy(6-isopropoxy-7-methoxy-4-oxo-2H-chromen-3(4H)-ylidene)acetate(6.0 mg, 0.0223 mol) in a mixture of ethanol (150 mL) and acetic acid(150, mL) was added 3-thienylhydrazine hydrochloride (2.7 g, 0.0223 mol)at RT under nitrogen. The reaction mixture was stirred at 100° C. for 4h. The reaction mixture was concentrated under high vacuum. The residuewas dissolved with ethyl acetate (20 mL), washed with water (20 mL),brine (20 mL), dried over sodium sulphate and concentrated under vacuum.The crude product was purified by column chromatography using petether/ethyl acetate as eluent to afford desired compound (6.5 g, 88%) asan off white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 8.02-8.01 (dd, J=1.2, 2.4 Hz, 1H), 7.86-7.83(dd, J=4, 16 Hz, 1H), 7.35-7.34 (dd, J=1.2, 4 Hz, 1H), 6.68 (s, 1H),6.19 (s, 1H), 5.40 (s, 2H), 4.31-4.26 (m, 2H), 3.94-3.88 (m, 1H), 3.72(s, 3H), 1.31-1.287 (m, 3H), 1.07 (s, 6H).

Step 8:8-Isopropoxy-7-methoxy-1-(3-thienyl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylicacid

To a solution of8-isopropoxy-7-methoxy-1-(3-thienyl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate(4 g, 0.0108 mol) in mixture of THF (70 mL), H₂O (20 mL), MeOH (10 mL)was added LiOH.H₂O (1.4 g, 0.0326 mol) at RT. The reaction mixture wasstirred at RT for 4 h. The reaction mixture was evaporated and acidifiedwith a solution of 1.5N HCl. The filtrate was dried under high vacuum toafford the desired compound (3.3 g, 79%) as an off white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 13.16 (bs, 1H), 8.01-8.00 (dd, J=1.2, 2.4Hz, 1H), 7.85-7.83 (dd, J=4, 16 Hz, 1H), 7.35-7.33 (dd, J=1.2, 4 Hz,1H), 6.69 (s, 1H), 6.19 (s, 1H), 5.39 (s, 2H), 3.94-3.88 (m, 2H), 3.72(s, 3H), 1.07 (s, 6H).

Step 9:8-Isopropoxy-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid tert-butyl-methyl-amide (19)

To a stirred solution of8-isopropoxy-7-methoxy-1-(3-thienyl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylicacid (1.1 g, 0.0028 mol) in DCM (50 mL) was added N-tert-butyl methylamine (0.3 g, 0.0034 mol), HATU (1.3 g, 0.0034 mol) and DIPEA (0.8 mL,0.0043 mol) at RT under nitrogen. The reaction mixture was stirred at RTfor 16 h. The reaction mixture was quenched to water (20 mL), extractedwith dichloromethane (2×100 mL). The combined organic layer was washedwith brine (100 mL) and dried over anhydrous sodium sulphate. Thesolvent was removed under vacuum; the crude product was purified bycolumn chromatography using pet ether/ethyl acetate (8:2) as eluent toafford the desired compound (1.1 g, 85%) as an off white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 7.97-7.96 (dd, J=1.2, 2.4 Hz, 1H), 7.82-7.80(dd, J=4, 16 Hz, 1H), 7.34-7.32 (dd, J=1.2, 4 Hz, 1H), 6.69 (s, 1H),6.22 (s, 1H), 5.27 (s, 2H), 3.39-3.89 (m, 1H), 3.72 (s, 3H), 3.14 (s,3H), 1.41 (s, 9H), 1.06 (s, 6H). m/z: 456 [M+H]⁺

The following compounds were prepared using procedures analogous tothose disclosed in example 7.

Compound Starting material LC/MS NMR

m/z: 526 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.53-7.46 (m, 2H), 7.25 (d,J = 4.9 Hz, 1H), 6.62 (s, 1H), 6.44 (d, J = 4.2 Hz, 1H), 5.50 (d, J =3.4 Hz, 2H), 4.39- 4.22 (m, 1H), 4.06 (dt, J = 12.9, 6.4 Hz, 1H), 3.83(s, 3H), 3.77 (dd, J = 11.0, 5.2 Hz, 1H), 3.69 (d, J = 5.5 Hz, 3H),3.60-3.50 (m, 1H), 2.63- 2.53 (m, 1H), 2.30-2.16 (m, 1H), 2.11-1.99 (m,2H), 1.87- 1.68 (m, 2H), 1.56 (d, J = 6.7 Hz, 1H), 1.47 (d, J = 6.7 Hz,1H), 1.22 (d, J = 6.1 Hz, 6H)

m/z: 512 [M + H]⁺ ¹H NMR (400 MHz, MeOD) δ 7.74 (d, J = 2.8Hz, 1H),7.72- 7.66 (m, 1H), 7.28 (dd, J = 3.2, 1.9 Hz, 1H), 6.64 (s, 1H), 6.37(d, J = 3.3 Hz, 1H), 5.36 (d, J = 3.0 Hz, 2H), 4.21 (ddt, J = 30.6,14.1, 4.9 Hz, 1H), 4.04 (dt, J = 12.1, 6.1 Hz, 1H), 3.96-3.82 (m, 2H),3.80 (s, 3H), 3.71-3.58 (m, 1H), 2.58- 2.44 (m, 1H), 2.24-2.11 (m, 1H),2.11-1.91 (m, 3H), 1.86-1.66 (m, 2H), 1.15 (d, J = 6.1 Hz, 6H).

The following compounds were prepared using procedures analogous tothose disclosed in example 1:

Compound Boronic acid Starting material Amine Starting material LC/MSNMR

m/z: 564 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.31 (d, J = 0.6 Hz, 1H),7.63 (d, J = 0.7 Hz, 1H), 7.58 (dd, J = 3.2, 1.4 Hz, 1H), 7.55-7.52 (m,1H), 7.28-7.26 (m, 1H), 6.96 (s, 1H), 6.67 (s, 1H), 5.53 (s, 2H), 3.92(s, 3H), 3.30 (s, 3H), 1.70 (s, 9H), 1.54 (s, 9H).

m/z = 509 [M + H]⁺ ¹H-NMR (DMSO- d6): δ 7.99 (s, 1H), 7.81 (s, 1H), 7.34(d, 1H), 6.83 (s, 1H), 6.66 (s, 1H), 5.42 (s, 2H), 3.78 (s, 3H), 3.17(s, 3H), 2.56 (s, 3H), 2.00 (s, 3H), 1.44 (s, 9H).

m/z = 498 [M + H]⁺ ¹H-NMR (CDCl₃): δ 7.57 (m, 2H), 7.02 (s, 1H),6.65-6.62 (m, 2H), 6.38 (s, 1H), 5.52 (s, 2H), 3.92 (s, 3H), 3.29 (s,3H), 1.54 (s, 9H).

m/z = 477 [M + H]⁺ ¹H-NMR (CDCl₃): δ 7.50 (s, 1H), 7.45 (d, 1H), 7.23(d, 1H), 6.83 (s, 1H), 6.67 (s, 2H), 6.15 (s, 1H), 5.94 (s, 1H), 5.51(s, 2H), 3.81 (s, 3H), 3.41 (s, 3H), 3.28 (s, 3H), 1.54 (s, 9H).

m/z = 478 [M + H]⁺ ¹H-NMR (DMSO- d6): δ 7.94 (s, 1H), 7.83 (d, 1H), 7.60(s, 1H), 7.48 (s, 1H), 7.32 (d, 1H), 6.76 (s, 1H), 6.50 (s, 1H), 5.38(s, 2H), 3.84 (s, 3H), 3.78 (s, 3H), 3.19 (s, 3H), 1.45 (s, 9H).

m/z = 507 [M + H]⁺ ¹H NMR (400 MHz, MeOD) δ 8.35 (t, J = 6.4 Hz, 1H),7.81 (s, 1H), 7.76 (d, J =3.7 Hz, 1H), 7.62 (s, 2H), 7.34 (d, J = 4.9Hz, 1H), 6.97 (s, 1H), 6.71 (s, 1H), 5.55 (s, 2H), 4.36 (t, J = 8.1 Hz,2H), 3.91 (s, 3H), 3.76 (t, J = 8.0 Hz, 2H), 3.63-3.54 (m, 2H),3.53-3.46 (m, 2H).

m/z = 478 [M + H]⁺ ¹H-NMR (DMSO- d6): δ 7.96 (s, 1H), 7.82-7.77 (m, 1H),7.40-7.32 (m, 2H), 6.87 (s, 1H), 6.61 (s, 1H), 6.01 (s, 1H), 5.44 (s,2H), 3.80 (s, 3H), 3.53 (s, 3H), 3.18 (s, 3H), 1.45 (s, 9H).

m/z = 464 [M + H]⁺ ¹H-NMR (DMSO- d6): δ 12.71 (s, 1H), 8.01-7.33 (m,4.5H), 6.96 (s, 0.5H), 6.81 (d, 1H), 6.56 (s, 0.5H), 5.97 (s, 0.5H),5.40 (d, 2H), 3.87 (d, 3H), 3.19 (s, 3H), 1.45 (s, 9H).

m/z = 478 [M + H]⁺ ¹H-NMR (DMSO- d6): δ 8.02 (s, 1H), 7.91 (d, 1H), 7.80(s, 1H), 7.38 (d, 1H), 7.21 (s, 1H), 6.85 (s, 1H), 6.77 (s, 1H), 5.38(s, 2H), 3.86 (s, 3H), 3.82 (s, 3H), 3.19 (s, 3H), 1.45 (s, 9H).

m/z = 493 [M + H]⁺ ¹H-NMR (DMSO- d6): δ 8.00 (s, 1H), 7.84-7.78 (m, 1H),7.36 (d, 1H), 6.84 (s, 1H), 6.48 (s, 1H), 5.43 (s, 2H), 3.78 (s, 3H),3.18 (s, 3H), 2.12 (s, 3H), 1.94 (s, 3H), 1.45 (s, 9H).

m/z = 493 [M + H]⁺ ¹H-NMR (DMSO- d6): δ 7.94 (s, 1H), 7.84-7.80 (m, 1H),7.33 (d, 1H), 6.68 (s, 1H), 6.56 (s, 1H), 5.63 (s, 1H), 5.35 (s, 2H),3.75 (s, 3H), 3.17 (s, 3H), 2.88 (s, 2H), 2.42 (t, 2H), 2.25-2.15 (m,5H), 1.44 (s, 9H).

m/z = 476 [M + H]⁺ ¹H-NMR (DMSO- d6): δ 9.08 (s, 1H), 8.69 (s, 2H), 8.00(s, 1H), 7.82 (t, 1H), 7.38 (d, J = 5.0 Hz, 1H), 6.91 (s, 1H), 6.74 (s,1H), 5.45 (s, 2H), 3.83 (s, 3H), 3.23-3.15 (m, 4H), 1.45 (s, 9H).

m/z = 478 [M + H]⁺ ¹H-NMR (DMSO- d6): δ 7.97 (s, 1H), 7.81 (s, 1H),7.41- 7.32 (m, 2H), 6.77 (s, 1H), 6.67 (s, 1H), 5.37 (s, 2H), 3.77 (s,3H), 3.18 (s, 3H), 1.95 (s, 3H), 1.45 (s, 9H).

m/z = 465 [M + H]⁺ ¹H-NMR (DMSO- d6): δ 9.04 (s, 1H), 8.33 (s, 1H), 8.02(s, 1H), 7.90 (s, 1H), 7.39 (d, 1H), 6.86 (d, 2H), 5.42 (s, 2H), 3.90(s, 3H), 3.19 (s, 3H), 1.45 (s, 9H).

m/z = 495 [M + H]⁺ ¹H-NMR (DMSO- d6): δ 8.03 (s, 1H), 7.93-7.87 (m, 1H),7.48 (s, 1H), 7.38 (d, 1H), 6.93 (s, 1H), 6.85 (s, 1H), 5.43 (s, 2H),3.89 (s, 3H), 3.19 (s, 3H), 2.61 (s, 3H), 1.45 (s, 9H).

¹H-NMR (DMSO- d6): δ 7.94 (s, 1H), 7.83 (s, 1H), 7.31 (d, 1H), 7.20 (s,1H), 6.82 (s, 1H), 5.47 (s, 2H), 4.40 (s, 1H), 4.08 (s, 1H), 3.88 (s,3H), 3.18 (s, 3H), 2.79 (t, 2H), 1.67- 1.59 (m, 2H), 1.44 (s, 9H).

m/z = 494 [M + H]⁺ ¹H-NMR (DMSO- d6): δ 7.97 (s, 1H), 7.81-7.76 (m, 1H),7.34 (d, 1H), 7.21 (d, 1H), 6.82-6.77 (m, 2H), 6.59 (s, 1H), 5.40 (s,2H), 3.75 (s, 3H), 3.18 (s, 3H), 2.12 (s, 3H), 1.45 (s, 9H).

m/z = 492 [M + H]⁺ ¹H-NMR (DMSO- d6): δ 7.98 (s, 1H), 7.79 (s, 1H), 7.34(d, 1H), 7.21 (s, 1H), 6.88 (s, 1H), 6.52 (s, 1H), 5.45 (d, 2H), 3.78(s, 3H), 3.45 (s, 3H), 3.18 (s, 3H), 1.71 (s, 3H), 1.45 (s, 9H).

m/z: 492 [M + H]⁺ ¹H NMR (400 MHz, MeOD) δ 7.85-7.80 (m, 3H), 7.79-7.73(m, 1H), 7.34 (d, J = 5.2 Hz, 1H), 6.99 (s, 1H), 6.78 (s, 1H), 5.42 (s,2H), 4.02- 3.96 (m, 2H), 3.93 (s, 3H), 3.87-3.81 (m, 2H), 1.54 (s, 6H).

m/z = 481 [M + H]⁺ ¹H-NMR (DMSO- d6): δ 8.99 (s, 1H), 7.95 (s, 2H), 7.85(s, 1H), 7.82-7.79 (m, 1H), 7.32 (d, 1H), 6.86 (s, 1H), 5.76 (s, 1H),5.41 (s, 2H), 4.09 (s, 5H), 3.93 (s, 3H), 3.19 (s, 3H), 1.45 (s, 9H).

m/z = 494 [M + H]⁺ ¹H-NMR (DMSO- d6): δ 7.97 (d, 1H), 7.81-7.76 (m, 1H),7.35 (dd, 2H), 6.87 (d, 1H), 6.82 (s, 1H), 6.67 (s, 1H), 5.42 (s, 2H),3.78 (s, 3H), 3.18 (s, 3H), 1.92 (s, 3H), 1.45 (s, 9H).

m/z = 492 [M + H]⁺ ¹H-NMR (DMSO- d6): δ 7.97-7.92 (m, 1H), 7.81-7.77 (m,1H), 7.33 (d, 1H), 6.83 (s, 1H), 6.59 (s, 1H), 6.45 (s, 1H), 5.42 (s,2H), 3.78 (s, 3H), 3.19 (d, 6H), 2.27 (s, 3H), 1.45 (s, 9H).

m/z = 494 [M + H]⁺ ¹H-NMR (DMSO- d6): δ 8.04-8.00 (m, 1H), 7.91-7.86 (m,IH), 7.37 (d, 1H), 6.96 (s, 1H), 6.83- 6.79 (m, 2H), 6.70 (d, 1H), 5.40(s, 2H), 3.87 (s, 3H), 3.19 (s, 3H), 2.41 (s, 3H), 1.45 (s, 9H).

m/z = 506 [M + H]⁺ ¹H-NMR (DMSO- d6): δ 7.96 (d, 1H), 7.82 (dd, 1H),7.60 (d, 1H), 7.46 (s, 1H), 7.32 (d, 1H), 6.76 (s, 1H), 6.49 (d, 1H),5.40 (s, 2H), 3.96 (t, 2H), 3.84 (s, 3H), 3.79-3.71 (m, 5H), 3.43 (s,2H), 1.43 (s, 6H).

m/z = 506 [M + H]⁺ ¹H-NMR (DMSO- d6): δ 12.41 (s, 1H), 7.97 (s, 1H),7.84- 7.79 (m, 1H), 7.45- 7.30 (m, 2H), 6.77 (s, 1H), 6.64 (s, 1H), 5.39(s, 2H), 3.95 (t, 2H), 3.79-3.70 (m, 5H), 3.42 (s, 2H), 1.94 (s, 3H),1.42 (s, 6H).

m/z = 505 [M + H]⁺ ¹H-NMR (DMSO- d6): δ 8.02 (dd, 1H), 7.89 (dd, 1H),7.37 (dd, 1H), 7.00 (s, 1H), 6.84 (s, 1H), 6.71 (s, 1H), 6.63 (t, 1H),5.79 (t, 1H), 5.37 (s, 2H), 3.96 (t, 2H), 3.84 (s, 3H), 3.73 (t, 2H),3.59 (s, 3H), 3.42 (s, 2H), 1.42 (s, 6H).

m/z = 477 [M + H]⁺ ¹H-NMR (DMSO- d6): δ 8.89 (s, 1H), 8.08 (dd, 1H),7.91 (dd, 1H), 7.41 (dd, 1H), 7.00 (t, 1H), 6.81 (s, 1H), 6.71 (s, 1H),6.63 (t, 1H), 5.78 (t, 1H), 5.48 (s, 2H), 4.71 (d, 2H), 4.32 (d, 2H),3.83 (s, 3H), 3.59 (s, 3H), 1.59 (s, 3H).

m/z = 478 [M + H]⁺ ¹H-NMR (DMSO- d6): δ 8.90 (s, 1H), 8.02 (dd, 1H),7.85 (dd, 1H), 7.60 (d, 1H), 7.42 (s, 1H), 7.35 (dd, 1H), 6.76 (s, 1H),6.49 (d, 1H), 5.52 (s, 2H), 4.71 (d, 2H), 4.32 (d, 2H), 3.84 (s, 3H),3.77 (s, 3H), 1.60 (s, 3H).

m/z = 505 [M + H]⁺ ¹H-NMR (DMSO- d6): δ 8.02 (d, 1H), 7.92-7.86 (m, 1H),7.38 (dd, 1H), 7.00 (s, 1H), 6.88 (d, 1H), 6.71 (s, 1H), 6.63 (t, 1H),5.80 (s, 1H), 5.39 (s, 2H), 4.54 (dd, 2H), 4.23-4.10 (m, 3H), 3.84 (s,3H), 3.72 (s, 1H), 3.59 (s, 3H), 3.35 (d, 3H), 2.98 (s, 1H), 1.27 (d,3H).

m/z = 506 [M + H]⁺ ¹H-NMR (DMSO- d6): δ 7.96 (d, 1H), 7.84 (s, 1H), 7.60(s, 1H), 7.50 (d, 1H), 7.32 (dd, 1H), 6.76 (s, 1H), 6.50 (s, 1H), 5.43(s, 2H), 4.55 (dd, 2H), 4.23-4.08 (m, 3H), 3.84 (s, 3H), 3.78 (s, 3H),3.72 (s, 1H), 3.37 (s, 3H), 3.18 (d, 1H), 2.99 (s, 1H), 1.27 (d, 3H).

m/z = 477 [M + H]⁺ ¹H-NMR (DMSO- d6): δ 8.05 (d, 1H), 7.91 (dd, 1H),7.40 (d, 1H), 7.00 (d, 1H), 6.87 (s, 1H), 6.71 (s, 1H), 6.64 (t, 1H),5.94 (s, 0.5H), 5.80 (s, 1H), 5.38 (s, 2H), 5.22 (s, 0.5H), 4.71 (s,4H), 3.84 (s, 3H), 3.59 (s, 3H), 3.41 (s, 1H), 3.24-3.12 (m, 2H).

m/z = 478 [M + H]⁺ ¹H-NMR (DMSO- d6): δ 7.99 (d, 1H), 7.84 (dd, 1H),7.60 (d, 1H), 7.49 (s, 1H), 7.35 (d, 1H), 6.76 (s, 1H), 6.50 (d, 1H),5.94 (s, 0.5H), 5.42 (s, 2H), 5.22 (s, 0.5H), 4.72 (s, 4H), 4.09 (q,1H), 3.84 (s, 3H), 3.78 (s, 3H), 3.41 (s, 1H), 3.18 (d, 5H).

m/z = 481 [M + H]⁺ ¹H-NMR (DMSO- d6): δ 8.45 (d, 1H), 8.08 (dd, 1H),7.94 (dd, 1H), 7.42 (dd, 1H), 7.15 (s, 1H), 7.02 (d, 1H), 6.95 (s, 1H),5.49 (s, 2H), 4.01 (s, 3H), 3.20 (s, 3H), 1.45 (s, 9H).

m/z = 506 [M + H]⁺ ¹H-NMR (DMSO- d6): δ 7.97 (dd, 1H), 7.79 (dd, 1H),7.38- 7.32 (m, 2H), 6.87 (s, 1H), 6.59 (s, 1H), 6.00 (d, 1H), 5.46 (s,2H), 3.99-3.92 (m, 2H), 3.80 (s, 3H), 3.73 (t, 2H), 3.52 (s, 3H), 3.42(s, 2H), 1.42 (s, 6H).

m/z = 478 [M + H]⁺ ¹H-NMR (DMSO- d6): δ 8.92 (s, 1H), 8.03 (dd, 1H),7.81 (dd, 1H), 7.39-7.35 (m, 2H), 6.87 (s, 1H), 6.56 (s, 1H), 5.99 (d,1H), 5.57 (s, 2H), 4.71 (d, 2H), 4.32 (d, 2H), 3.80 (s, 3H), 3.52 (s,3H), 1.59 (s, 3H).

m/z = 506 [M + H]⁺ ¹H-NMR (DMSO- d6): δ 7.97 (dd, 1H), 7.80 (dd, 1H),7.39- 7.31 (m, 2H), 6.86 (s, 1H), 6.62 (d, 1H), 6.03-6.00 (d, 1H), 5.48(s, 2H), 4.54 (dd, 2H), 4.25-4.09 (m, 3H), 3.80 (s, 3H), 3.72 (s, 1H),3.52 (s, 3H), 3.36 (s, 2H), 2.99 (s, 1H), 1.26 (d, 3H).

m/z = 494 [M + H]⁺ ¹H-NMR (DMSO- d6): δ 8.73 (s, 1H), 8.02 (dd, 1H),7.82 (dd, 1H), 7.37 (dd, 2H), 6.87 (s, 1H), 6.56 (s, 1H), 5.99 (d, 1H),5.56 (s, 2H), 5.15 (s, 1H), 4.68 (d, 2H), 4.52 (d, 2H), 3.80 (s, 3H),3.69 (s, 2H), 3.52 (s, 3H).

m/z: 533 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.50 (dd, J = 3.2, 1.4 Hz,1H), 7.44 (dd, J = 5.1, 3.2 Hz, 1H), 7.24 (dd, J = 5.1, 1.4 Hz, 1H),6.81 (s, 1H), 6.66 (s, 1H), 5.83 (s, 1H), 5.47 (s, 2H), 4.11-4.05 (m,2H), 3.89-3.83 (m, 2H), 3.82 (s, 3H), 3.50 (s, 2H), 3.39 (s, 3H), 2.22(s, 3H), 2.01 (s, 3H), 1.27 (s, 6H).

m/z: 534 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.49 (dd, J = 3.1, 1.2 Hz,1H), 7.44 (dd, J = 5.0, 3.3 Hz, 1H), 7.21 (dd, J = 5.1, 1.2 Hz, 1H),6.68 (s, 1H), 6.63 (s, 1H), 5.51 (s, 2H), 4.12- 4.05 (m, 2H), 3.90- 3.84(m, 2H), 3.80 (s, 3H), 3.74 (s, 3H), 3.50 (s, 2H), 2.01 (d, J = 5.5 Hz,6H), 1.55 (s, 6H).

m/z: 520 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.50-7.47 (m, 1H), 7.47-7.44(m, 1H), 7.19 (dd, J = 5.0, 1.5 Hz, 1H), 6.72 (s, 1H), 6.68 (s, 1H),5.83 (s, 1H), 5.53 (s, 2H), 4.09 (dd, J = 8.4, 3.0 Hz, 2H), 3.88- 3.83(m, 2H), 3.82 (s, 3H), 3.56 (s, 3H), 3.49 (s, 2H), 2.27 (s, 3H), 1.54(s, 6H).

m/z: 520 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.51 (dd, J = 3.2, 1.3 Hz,1H), 7.46 (dd, J = 5.1, 3.3 Hz, 1H), 7.37 (s, 1H), 7.22 (dd, J = 5.1,1.3 Hz, 1H), 6.84 (s, 1H), 6.67 (s, 1H), 5.50 (s, 2H), 4.13-4.06 (m,2H), 3.89-3.82 (m, 8H), 3.50 (s, 2H), 2.03 (s, 3H), 1.55 (s, 6H).

m/z: 520 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.53-7.49 (m, 1H), 7.49-7.44(m, 1H), 7.35 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 6.70 (s, 1H), 6.67 (s,1H), 5.50 (s, 2H), 4.13-4.05 (m, 2H), 3.90-3.83 (m, 2H), 3.81 (d, J =8.9 Hz, 6H), 3.50 (s, 2H), 2.07 (s, 3H), 1.55 (s, 6H).

m/z: 505 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.62 (d, J = 7.3 Hz, 1H),7.51- 7.42 (m, 2H), 7.22 (d, J = 5.0 Hz, 1H), 6.83 (s, 1H), 6.67 (s,1H), 6.17-6.12 (m, 1H), 5.96-5.89 (m, 1H), 5.51 (s, 2H), 4.15- 4.05 (m,2H), 3.91- 3.84 (m, 2H), 3.82 (s, 3H), 3.50 (s, 2H), 3.41 (s, 3H), 1.55(s, 6H).

m/z: 520 [M + H]⁺ ¹H NMR (400 MHz, MeOD) δ 7.79-7.74 (m, 1H), 7.66 (dd,J = 5.0, 3.2 Hz, 1H), 7.27 (d, J = 5.1 Hz, 1H), 6.76 (s, 1H), 6.58 (s,1H), 5.42 (s, 2H), 4.01-3.95 (m, 2H), 3.86-3.80 (m, 2H), 3.79 (s, 3H),3.51 (s, 2H), 2.01 (s, 6H), 1.53 (s, 6H).

m/z = 478 [M + H]⁺ ¹H-NMR (DMSO- d6): δ 7.89 (dd, 1H), 7.79 (dd, 1H),7.74 (s, 1H), 7.47 (s, 1H), 7.39 (d, 1H), 7.30 (dd, 1H), 6.76 (s, 1H),5.33 (s, 2H), 3.89 (s, 3H), 3.64 (s, 3H), 3.18 (s, 3H), 1.45 (s, 9H).

m/z = 478 [M + H]⁺ ¹H-NMR (DMSO- d6): δ 7.95 (d, 1H), 7.79 (dd, 1H),7.59 (s, 1H), 7.35-7.32 (m, 1H), 6.84 (s, 1H), 6.62 (d, 2H), 5.42 (s,2H), 3.79 (s, 3H), 3.35 (s, 3H), 3.18 (s, 3H), 1.45 (s, 9H).

m/z = 465 [M + H]⁺ ¹H-NMR (DMSO- d6): δ 8.07 (d, 1H), 7.98 (dd, 1H),7.83 (dd, 1H), 7.37-7.33 (m, 2H), 7.24 (d, 1H), 6.88 (s, 1H), 5.46 (s,2H), 3.87 (s, 3H), 3.19 (s, 3H), 1.45 (s, 9H).

m/z = 493 [M + H]⁺ ¹H-NMR (DMSO- d6): δ 7.96 (dd, 1H), 7.83 (dd, 1H),7.33 (dd, 1H), 6.68 (s, 1H), 6.54 (s, 1H), 5.67-5.63 (m, 1H), 5.36 (s,2H), 3.75 (s, 3H), 3.17 (s, 3H), 2.85 (d, 2H), 2.38 (t, 2H), 2.22 (s,3H), 2.14 (d, 2H), 1.44 (s, 9H).

m/z = 478 [M + H]⁺ ¹H-NMR (DMSO- d6): δ 12.45 (s, 1H), 8.43 (d, 1H),8.03 (dd, 1H), 7.82 (dd, 1H), 7.37 (dd, 2H), 6.76 (s, 1H), 6.62 (s, 1H),5.52 (s, 2H), 4.49-4.40 (m, 1H), 3.86-3.67 (m, 6H), 3.56 (dd, 1H), 2.17-2.06 (m, 1H), 2.02- 1.91 (m, 4H).

m/z = 477 [M + H]⁺ ¹H-NMR (DMSO- d6): δ 8.50 (dd, 1H), 8.09-8.03 (m,1H), 7.90 (dd, 1H), 7.40 (d, 1H), 7.00 (s, 1H), 6.82 (d, 1H), 6.70 (s,1H), 6.63 (s, 1H), 5.78 (s, 1H), 5.48 (s, 2H), 4.97 (dd, 1H), 4.53-4.43(m, 1H), 4.32-4.24 (m, 1H), 3.89-3.76 (m, 4H), 3.59 (s, 3H), 2.37- 2.29(m, 1H), 2.15- 2.07 (m, 1H), 2.03- 1.91 (m, 1H).

m/z = 478 [M + H]⁺ ¹H-NMR (DMSO- d6): δ 8.50 (dd, 1H), 8.00 (s, 1H),7.88- 7.80 (m, 1H), 7.60 (d, 1H), 7.43 (d, 1H), 7.34 (d, 1H), 6.75 (s,1H), 6.49 (d, 1H), 5.52 (s, 2H), 4.99 (s, 1H), 4.54-4.43 (m, 1H),4.33-4.24 (m, 1H), 3.94-3.70 (m, 7H), 2.39-2.28 (m, 1H), 2.16-2.06 (m,1H), 2.04-1.91 (m, 1H).

m/z = 478 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 8.50 (dd, 1H), 8.06- 8.01 (m,1H), 7.82 (dd, 1H), 7.40-7.35 (m, 2H), 6.76 (s, 1H), 6.62 (d, 1H), 5.51(d, 2H), 4.97 (s, 1H), 4.51-4.44 (m, 1H), 4.31-4.23 (m, 1H), 3.90-3.74(m, 5H), 2.37-2.29 (m, 1H), 2.15-2.06 (m, 1H), 2.02-1.90 (m, 4H).

m/z: 546 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.61-7.48 (m, 3H), 7.32 (d,J = 2.0 Hz, 1H), 6.66 (s, 1H), 6.54 (d, J = 1.9 Hz, 1H), 6.36 (s, 1H),5.69-5.49 (m, 2H), 5.31 (d, J = 13.8 Hz, 1H), 4.44- 4.22 (m, 2H), 4.04(dd, J = 43.8, 13.6 Hz, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.84-3.70 (m,1H), 3.62 (dd, J = 24.9, 12.6 Hz, 1H), 3.36 (t, J = 14.2 Hz, 1H).

468 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 7.99 (dd, 1H), 7.85 (dd, 1H), 7.35 (dd,1H), 6.80 (s, 1H), 6.71 (s, 1H), 6.61 (d, 1H), 5.63 (dt, 1H), 5.37 (d,2H), 3.93 (dd, 2H), 3.80 (s, 3H), 3.23 (s, 3H), 3.18 (s, 3H), 1.44 (s,9H).

m/z = 480 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 7.92 (dd, 1H), 7.82 (dd, 1H),7.30 (dd, 1H), 6.93 (s, 1H), 6.69 (s, 1H), 5.38 (s, 2H), 5.29 (t, 1H),3.89 (t, 2H), 3.78 (s, 3H), 3.18 (s, 3H), 2.12-2.03 (m, 2H), 1.74(quintet, 2H), 1.44 (s, 9H).

m/z = 464 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 7.97 (dd, 1H), 7.85 (dd, 1H),7.34 (dd, 1H), 6.71 (s, 1H), 6.68 (s, 1H), 6.28 (s, 1H), 5.38 (s, 2H),3.82 (s, 3H), 3.18 (s, 3H), 2.46-2.38 (m, 2H), 2.29-2.19 (m, 2H), 1.76(quintet, 2H), 1.44 (s, 9H).

m/z = 492 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 7.97 (dd, 1H), 7.80 (dd, 1H),7.56 (s, 1H), 7.33 (dd, 1H), 6.77 (s, 1H), 6.72 (s, 1H), 5.37 (s, 2H),3.77 (s, 3H), 3.73 (s, 3H), 3.17 (s, 3H), 1.84 (s, 3H), 1.44 (s, 9H).

m/z = 466 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 7.98 (dd, 1H), 7.88 (dd, 1H),7.34 (dd, 1H), 6.77 (s, 1H), 6.44 (s, 1H), 6.34 (t, 1H), 5.41 (s, 2H),4.69-4.62 (m, 2H), 4.49-4.41 (m, 2H), 3.85 (s, 3H), 3.18 (s, 3H), 1.44(s, 9H).

m/z = 523 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 7.92 (dd, 1H), 7.76 (dd, 1H),7.60 (s, 1H), 7.30 (dd, 1H), 6.91 (s, 1H), 6.67 (s, 1H), 5.48 (s, 2H),5.45 (s, 2H), 3.79 (s, 3H), 3.27 (q, 2H), 3.18 (s, 3H), 1.45 (s, 9H),0.92 (t, 3H).

m/z = 478 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 8.21 (s, 1H), 7.95 (dd, 1H), 7.82(dd, 1H), 7.72 (s, 1H), 7.33 (dd, 1H), 6.84 (s, 1H), 5.39 (s, 2H), 4.04(s, 3H), 3.91 (s, 3H), 3.19 (s, 3H), 1.45 (s, 9H).

m/z: 520 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.58 (d, J = 2.0 Hz, 1H),7.53- 7.49 (m, 2H), 7.32 (d, J = 2.0 Hz, 1H), 7.27 (s, 1H), 6.67 (s,1H), 6.54 (d, J = 2.1 Hz, 1H), 5.54 (s, 2H), 4.90 (s, 2H), 4.57 (d, J =6.6 Hz, 2H), 4.17 (s, 3H), 3.90 (s, 3H), 3.88 (s, 3H), 3.63 (t, J = 4.5Hz, 2H).

m/z: 518 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.59-7.53 (m, 2H), 7.30 (d,J = 1.5 Hz, 1H), 7.06 (s, 1H), 7.01 (s, 1H), 6.65 (s, 1H), 6.55 (t, J =2.4 Hz, 1H), 6.04 (s, 1H), 5.55 (s, 2H), 4.40- 4.25 (m, 2H), 3.89 (s,3H), 3.86-3.70 (m, 4H), 3.67 (s, 3H), 3.59 (s, 2H), 2.16 (d, J = 7.8 Hz,3H).

m/z: 605 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.55 (dd, J = 3.2, 1.3 Hz,1H), 7.53- 7.47 (m, 2H), 7.32 (d, J = 2.2 Hz, 1H), 7.29-7.24 (m, 1H),6.67 (s, 1H), 6.54 (d, J = 2.2 Hz, 1H), 5.52 (s, 2H), 4.35-4.26 (m, 2H),3.89 (s, 3H), 3.88 (s, 3H), 3.61-3.47 (m, 4H), 1.61 (s, 6H), 1.50 (s,9H).

m/z: 604 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.58-7.51 (m, 2H), 7.28 (d,J = 1.5 Hz, 1H), 7.05 (s, 1H), 7.00 (t, J = 1.9 Hz, 1H), 6.64 (s, 1H),6.55 (t, J = 2.5 Hz, 1H), 6.04 (s, 1H), 5.49 (s, 2H), 4.34-4.26 (m, 2H),3.90 (s, 3H), 3.66 (s, 3H), 3.61- 3.47 (m, 4H), 1.61 (s, 6H), 1.50 (s,9H).

m/z: 603 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.59-7.48 (m, 3H), 7.32 (d,J = 2.1 Hz, 1H), 7.28- 7.25 (m, 1H), 6.66 (s, 1H), 6.54 (d, J = 2.1 Hz,1H), 5.54 (s, 2H), 4.42-4.23 (m, 2H), 3.90 (s, 3H), 3.88 (s, 4H),3.63-3.41 (m, 4H), 1.61 (s, 3H), 1.48 (s, 9H).

m/z: 519 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.56 (dd, J = 3.2, 1.4 Hz,1H), 7.52 (s, 1H), 7.48 (dd, J = 5.1, 3.2 Hz, 1H), 7.32 (d, J = 2.2 Hz,1H), 7.27 (d, J = 1.3 Hz, 1H), 6.66 (s, 1H), 6.53 (d, J = 2.2 Hz, 1H),5.48 (s, 2H), 4.05- 3.97 (m, 2H), 3.89 (s, 3H), 3.88 (s, 3H), 2.56- 2.51(m, 2H), 2.33- 2.29 (m, 5H), 1.59 (s, 6H).

m/z: 518 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.56 (dd, J = 3.2, 1.4 Hz,1H), 7.52 (dd, J = 5.0, 3.3 Hz, 2H), 7.06 (s, 1H), 7.00 (t, J = 1.9 Hz,1H), 6.64 (s, 1H), 6.55 (t, J = 2.5 Hz, 1H), 6.06- 6.01 (m, 1H), 5.46(s, 2H), 4.03-3.97 (m, 2H), 3.90 (s, 3H), 3.66 (s, 3H), 2.55-2.49 (m,2H), 2.30 (s, 5H), 1.59 (s, 6H).

m/z = 493 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 8.31 (t, 1H), 8.08 (dd, 1H), 7.91(dd, 1H), 7.41 (dd, 1H), 7.00 (t, 1H), 6.81 (s, 1H), 6.71 (s, 1H), 6.63(t, 1H), 5.89 (s, 1H), 5.80-5.75 (m, 1H), 5.51 (s, 2H), 4.48 (d, 2H),4.38 (d, 2H), 3.84 (s, 3H), 3.61-3.53 (m, 5H).

494 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 8.32 (t, 1H), 8.03 (dd, 1H), 7.85 (dd,1H), 7.60 (d, 1H), 7.42 (s, 1H), 7.35 (dd, 1H), 6.76 (s, 1H), 6.49 (d,1H), 5.88 (s, 1H), 5.55 (s, 2H), 4.48 (d, 2H), 4.38 (d, 2H), 3.84 (s,3H), 3.77 (s, 3H), 3.56 (d, 2H).

m/z: 505 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.39 (s, 1H), 7.63-7.36 (m,2H), 7.35-7.31 (m, 2H), 6.67 (s, 1H), 6.54 (s, 1H), 5.50 (s, 2H), 4.13(s, 1H), 3.89 (s, 3H), 3.77-3.62 (m, 1H), 3.21 (s, 1H), 3.16- 3.05 (m,2H), 2.94 (s, 1H), 1.64 (s, 3H), 1.51- 1.42 (m, 6H).

m/z: 504 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.54 (dd, J = 8.0, 2.4 Hz,2H), 7.27 (d, J = 5.0 Hz, 1H), 7.05 (s, 1H), 7.00 (s, 1H), 6.64 (s, 1H),6.55 (d, J = 2.2 Hz, 1H), 6.03 (d, J = 1.7 Hz, 1H), 5.48 (s, 2H), 4.28(s, 2H), 3.89 (s, 3H), 3.66 (s, 3H), 3.34 (s, 2H), 3.07 (s, 2H), 1.69(s, 6H).

m/z: 503 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.26 (s, 1H), 7.61-7.46 (m,3H), 7.35-7.31 (m, 1H), 6.67 (s, 1H), 6.54 (s, 1H), 5.54 (s, 2H), 4.37(m, 2H), 3.93-3.85 (m, 6H), 3.20-2.99 (m, 4H), 1.16-0.95 (m, 4H).

m/z = 492 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 8.11 (d, 1H), 8.00 (s, 1H), 7.84(s, 1H), 7.60 (s, 1H), 7.42 (s, 1H), 7.34 (s, 1H), 6.76 (s, 1H), 6.49(s, 1H), 5.54 (s, 2H), 4.75 (s, 1H), 4.32 (s, 1H), 4.15 (s, 1H), 3.84(s, 3H), 3.78 (s, 3H), 2.06-1.85 (m, 2H), 1.78-1.53 (m, 4H).

m/z = 491 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 8.14-8.04 (m, 2H), 7.91 (s, 1H),7.39 (s, 1H), 7.00 (s, 1H), 6.80 (s, 1H), 6.71 (s, 1H), 6.63 (s, 1H),5.78 (s, 1H), 5.50 (s, 2H), 4.75 (s, 1H), 4.33 (s, 1H), 4.15 (s, 1H),3.84 (s, 3H), 3.59 (s, 3H), 2.06-1.84 (m, 2H), 1.78-1.52 (m, 4H).

m/z = 504 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 7.96 (s, 1H), 7.84 (s, 1H), 7.60(s, 1H), 7.49 (s, 1H), 7.32 (s, 1H), 6.78 (s, 1H), 6.50 (s, 1H), 5.55(s, 2H), 5.45 (s, 2H), 4.31 (s, 2H), 3.91 (s, 2H), 3.85 (s, 3H), 3.78(s, 3H), 2.29 (s, 2H), 1.75 (s, 2H).

m/z = 505 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 8.01 (s, 1H), 7.89 (d, 1H), 7.37(s, 1H), 7.00 (s, 1H), 6.85 (s, 1H), 6.71 (s, 1H), 6.63 (s, 1H), 5.80(s, 1H), 5.44 (s, 2H), 4.88 (s, 1H), 4.10 (s, 1H), 3.91- 3.80 (m, 5H),3.59 (s, 4H), 2.15-2.06 (m, 1H), 1.89-1.72 (m, 2H), 1.64-1.54 (m, 1H),1.40 (s, 3H).

m/z = 507 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 8.06 (dd, 1H), 7.91 (dd, 1H),7.80 (s, 1H), 7.39 (dd, 1H), 7.00 (t, 1H), 6.81 (s, 1H), 6.71 (s, 1H),6.63 (t, 1H), 5.78 (dd, 1H), 5.49 (s, 2H), 5.10 (s, 1H), 3.91- 3.75 (m,8H), 3.63- 3.56 (m, 5H), 2.35- 2.27 (m, 1H), 2.02- 1.93 (m, 1H).

m/z = 494 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 8.23 (s, 1H), 8.02 (dd, 1H), 7.86(dd, 1H), 7.60 (d, 1H), 7.42 (s, 1H), 7.34 (dd, 1H), 6.76 (s, 1H), 6.49(d, 1H), 5.54 (s, 2H), 5.18 (s, 1H), 3.84 (s, 3H), 3.77 (s, 3H),3.44-3.36 (m, 4H), 1.05 (s, 3H).

m/z = 545 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 8.04 (dd, 1H), 7.97 (s, 1H), 7.91(dd, 1H), 7.39 (dd, 1H), 7.28 (s, 1H), 6.85 (s, 1H), 6.79 (s, 1H), 5.41(s, 2H), 4.38 (t, 2H), 3.99- 3.94 (m, 2H), 3.87 (s, 3H), 3.76-3.71 (m,2H), 3.43 (s, 2H), 3.06 (t, 2H), 1.43 (s, 6H).

m/z = 534 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 8.04 (dd, 1H), 7.92 (dd, 1H),7.78 (s, 1H), 7.39 (dd, 1H), 7.26 (s, 1H), 6.82 (s, 1H), 6.76 (s, 1H),5.41 (s, 2H), 4.48 (septet, 1H), 3.97 (t, 2H), 3.86 (s, 3H), 3.73 (t,2H), 3.43 (s, 2H), 1.44-1.39 (m, 12H).

m/z = 548 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 8.04 (dd, 1H), 7.91 (dd, 1H),7.78 (s, 1H), 7.39 (dd, 1H), 7.25 (s, 1H), 6.83 (s, 1H), 6.77 (s, 1H),5.40 (s, 2H), 3.99-3.94 (m, 2H), 3.91-3.84 (m, 5H), 3.76-3.71 (m, 2H),3.43 (s, 2H), 2.08 (septet, 1H), 1.43 (s, 6H), 0.84 (d, 6H).

m/z = 534 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 8.05 (dd, 1H), 7.92 (dd, 1H),7.78 (s, 1H), 7.39 (dd, 1H), 7.26 (s, 1H), 6.82 (s, 1H), 6.76 (s, 1H),5.41 (s, 2H), 4.48 (septet, 1H), 4.00- 3.94 (m, 2H), 3.86 (s, 3H),3.76-3.71 (m, 2H), 3.43 (s, 2H), 1.45-1.39 (m, 12H).

m/z = 605 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 8.04 (dd, 1H), 7.92- 7.85 (m,2H), 7.39 (dd, 1H), 7.22 (s, 1H), 6.83 (s, 1H), 6.77 (s, 1H), 5.40 (s,2H), 4.20 (t, 2H), 3.99-3.94 (m, 2H), 3.86 (s, 3H), 3.76-3.71 (m, 2H),3.58-3.53 (m, 4H), 3.42 (s, 2H), 2.71-2.65 (m, 2H), 2.43-2.38 (m, 4H),1.42 (s, 6H).

m/z = 563 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 8.04 (dd, 1H), 7.91 (dd, 1H),7.82 (s, 1H), 7.39 (dd, 1H), 7.23 (s, 1H), 6.82 (s, 1H), 6.76 (s, 1H),5.40 (s, 2H), 4.16 (t, 2H), 3.98- 3.94 (m, 2H), 3.86 (s, 3H), 3.76-3.71(m, 2H), 3.42 (s, 2H), 2.62 (t, 2H), 2.16 (s, 6H), 1.42 (s, 6H).

m/z = 548 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 7.98 (dd, 1H), 7.79 (dd, 1H),7.34 (dd, 1H), 6.77 (s, 1H), 6.46 (s, 1H), 5.40 (s, 2H), 3.97-3.91 (m,4H), 3.75-3.70 (m, 5H), 3.42 (s, 2H), 1.92 (s, 3H), 1.82 (s, 3H), 1.42(s, 6H), 1.27 (t, 3H).

580 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 8.04 (dd, 1H), 7.90 (dd, 1H), 7.83 (s,1H), 7.38 (dd, 1H), 7.25 (s, 1H), 6.83 (s, 1H), 6.77 (s, 1H), 5.40 (s,2H), 4.52 (s, 2H), 4.26 (t, 2H), 3.96 (t, 2H), 3.86 (s, 3H), 3.80 (t, J= 5.3 Hz, 2H), 3.73 (t, 2H), 3.42 (s, 2H), 3.16 (s, 3H), 1.42 (s, 6H).

m/z = 589 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 8.04 (dd, 1H), 7.90 (dd, 1H),7.83 (s, 1H), 7.39 (dd, 1H), 7.23 (s, 1H), 6.83 (s, 1H), 6.76 (s, 1H),5.40 (s, 2H), 4.18 (t, 2H), 3.98-3.94 (m, 2H), 3.86 (s, 3H), 3.75-3.71(m, 2H), 3.42 (s, 2H), 2.79 (t, 2H), 2.47-2.43 (m, 4H), 1.69-1.64 (m,4H), 1.42 (s, 6H).

m/z = 532 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 8.03 (dd, 1H), 7.90 (dd, 1H),7.79 (s, 1H), 7.38 (dd, 1H), 7.26 (s, 1H), 6.82 (s, 1H), 6.77 (s, 1H),6.06-5.95 (m, 1H), 5.40 (s, 2H), 5.24-5.11 (m, 2H), 4.73 (d, 2H), 3.98-3.94 (m, 2H), 3.85 (s, 3H), 3.75-3.71 (m, 2H), 3.42 (s, 2H), 1.42 (s,6H).

m/z = 564 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 8.04 (dd, 1H), 7.91 (dd, 1H),7.80 (s, 1H), 7.39 (dd, 1H), 7.23 (s, 1H), 6.83 (s, 1H), 6.77 (s, 1H),5.40 (s, 2H), 4.12 (t, 2H), 3.99- 3.94 (m, 2H), 3.86 (s, 3H), 3.76-3.70(m, 2H), 3.42 (s, 2H), 3.29- 3.23 (m, 5H), 1.98 (quintet, 2H), 1.42 (s,6H).

m/z = 578 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 8.04 (dd, 1H), 7.90 (dd, 1H),7.80 (s, 1H), 7.39 (dd, 1H), 7.26 (s, 1H), 6.82 (s, 1H), 6.77 (s, 1H),5.40 (s, 2H), 5.14 (t, 1H), 4.22 (d, 2H), 3.99-3.94 (m, 2H), 3.88-3.81(m, 7H), 3.76-3.71 (m, 2H), 3.42 (s, 2H), 1.42 (s, 6H).

m/z = 520 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 8.04 (dd, 1H), 7.91 (dd, 1H),7.81 (s, 1H), 7.38 (dd, 1H), 7.22 (s, 1H), 6.83 (s, 1H), 6.76 (s, 1H),5.40 (s, 2H), 4.14-4.06 (m, 6H), 3.98-3.94 (m, 2H), 3.86 (s, 3H), 3.76-3.71 (m, 2H), 3.42 (s, 2H), 1.42 (s, 6H), 1.36 (t, 3H).

m/z = 534 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 8.04 (dd, 1H), 7.91 (dd, 1H),7.80 (s, 1H), 7.39 (dd, 1H), 7.23 (s, 1H), 6.83 (s, 1H), 6.76 (s, 1H),5.40 (s, 2H), 4.03 (t, 2H), 3.99- 3.94 (m, 2H), 3.86 (s, 3H), 3.76-3.71(m, 2H), 3.42 (s, 2H), 1.77 (sextet, 2H), 1.42 (s, 6H), 0.82 (t, 3H).

m/z = 548 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 7.94 (dd, 1H), 7.76 (dd, 1H),7.30 (dd, 1H), 6.84 (s, 1H), 6.55 (s, 1H), 5.76 (s, 1H), 5.43 (s, 2H),3.96- 3.91 (m, 2H), 3.77- 3.70 (m, 5H), 3.60 (t, 2H), 3.42 (s, 2H), 2.12(s, 3H), 1.54 (sextet, 2H), 1.42 (s, 6H), 0.62 (t, 3H).

m/z = 520 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 7.96 (dd, 1H), 7.77 (dd, 1H),7.40 (d, 1H), 7.32 (dd, 1H), 6.87 (s, 1H), 6.56 (s, 1H), 5.97 (d, 1H),5.45 (s, 2H), 3.97-3.93 (m, 2H), 3.80-3.71 (m, 7H), 3.42 (s, 2H), 1.42(s, 6H), 1.17 (t, 3H).

Example 87-Methoxy-8-(2-methyl-propenyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid methyl-[2-(2-oxo-oxazolidin-3-yl)-ethyl]-amide (23)

To7-methoxy-8-(2-methyl-propenyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid [2-(2-oxo-oxazolidin-3-yl)-ethyl]-amide (22.00 mg; 0.04 mmol; 1.00eq.) was added N,N-Dimethyl-formamide (0.50 ml) and sodium hydride (2.67mg; 0.07 mmol; 1.50 eq.). Reaction was stirred at RT for 10 min theniodomethane (0.00 ml; 0.05 mmol; 1.10 eq.) (1 drop) was added and thereaction was stirred at RT for 15 min. Water was added and product wasextracted with EtOAc and washed with water. Organic layer was dried,filtered, concentrated. Residue was dried on high vacuum thenlyophilized to afford the desired product (22.5 mg, 99%) as an off whitesolid.

¹H NMR (400 MHz, CDCl₃) δ 7.56-7.42 (m, 2H), 7.24 (d, J=4.9 Hz, 1H),6.73 (d, J=4.0 Hz, 1H), 6.57 (d, J=2.8 Hz, 1H), 6.12 (s, 1H), 5.55 (s,1H), 5.51 (s, 1H), 4.38-4.31 (m, 1H), 4.20-4.10 (m, 2H), 3.82 (s, 3H),3.81-3.72 (m, 2H), 3.62-3.55 (m, 3H), 3.53 (s, 1H), 3.46-3.38 (m, 1H),3.17 (s, 1H), 1.85 (s, 3H), 1.53 (d, J=3.8 Hz, 3H). m/z: 509 [M+H]⁺

The following compounds were prepared using procedures analogous tothose disclosed in example 8 above:

Compound Starting material LC/MS NMR

m/z: 539 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.60-7.47 (m, 2H), 7.26 (dd,J = 5.0, 1.4 Hz, 1H), 6.61 (s, 1H), 6.41 (d, J = 3.6 Hz, 1H), 5.54-5.45(m, 2H), 4.10-4.00 (m, 1H), 3.98- 3.86 (m, 1H), 3.84 (s, 3H), 3.60-3.51(m, 1H), 3.51- 3.42 (m, 2H), 3.33-3.25 (m, 1H), 3.15-3.10 (m, 1H), 2.95(s, 3H), 2.73 (s, 2H), 2.42-2.23 (m, 2H), 2.23- 2.04 (m, 2H), 2.04-1.79(m, 2H), 1.22 (d, J = 6.1 Hz, 6H). 8-Isopropoxy-7-methoxy-1-thiophen-3-yl-1,4-dihydro- chromeno[4,3-c]pyrazole-3- carboxylic acid[2- (cyclobutanecarbonyl-methyl- amino)-ethyl]-methyl-amide (29)

m/z: 553 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.59-7.44 (m, 2H), 7.26 (dd,J = 5.0, 1.4 Hz, 1H), 6.61 (s, 1H), 6.44-6.32 (m, 1H), 5.59-5.36 (m,2H), 4.10- 4.01 (m, 1H), 3.91 (dd, J = 19.2, 11.5 Hz, 2H), 3.84 (s, 3H),3.59-3.51 (m, 1H), 3.47 (dd, J = 19.7, 6.8 Hz, 2H), 3.38 (t, J = 7.2 Hz,1H), 3.33-3.26 (m, 1H), 3.16- 3.06 (m, 3H), 2.95 (s, 2H), 2.73 (s, 1H),2.43-2.22 (m, 2H), 2.21-2.06 (m, 2H), 2.06-1.76 (m, 2H), 1.22 (d, J =6.1 Hz, 6H). 8-Isopropoxy-7-methoxy-1- thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3- carboxylic acid [3-(cyclobutanecarbonyl-methyl- amino)-propyl]-methyl-amide (30)

m/z: 482 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.52 (dd, J = 3.2, 1.4 Hz,1H), 7.46 (dd, J = 5.1, 3.2 Hz, 1H), 7.23 (dd, J = 5.1, 1.4 Hz, 1H),6.74 (s, 1H), 6.58 (s, 1H), 6.12 (s, 1H), 5.45 (s, 2H), 3.82 (s, 3H),3.78 (s, 2H), 3.39 (s, 3H), 3.33 (s, 3H), 1.85 (s, 3H), 1.53 (d, J = 1.1Hz, 3H), 1.51 (s, 6H). 7-Methoxy-8-(2-methyl-propenyl)-1-thiophen-3-yl-1,4- dihydro-chromeno[4,3-c]pyrazole-3-carboxylic acid (2-methoxy-1,1-dimethyl-ethyl)-methyl-amide (31)

m/z: 509 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.57-7.46 (m, 2H), 7.27-7.19 (m, 1H), 6.74 (s, 1H), 6.57 (s, 1H), 6.12 (s, 1H), 5.61-5.50 (m,2H), 3.97- 3.87 (m, 2H), 3.82 (s, 3H), 3.53 (dd, J = 23.0, 9.4 Hz, 4H),3.38 (d, J = 6.5 Hz, 2H), 3.28 (s, 1H), 3.12 (d, J = 7.8 Hz, 3H), 2.97(d, J = 5.7 Hz, 2H), 2.81 (d, J = 12.9 Hz, 1H), 1.85 (s, 3H), 1.53 (s,3H). 7-Methoxy-8-(2-methyl- propenyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3- c]pyrazole-3-carboxylic acid[3-(acetyl-methyl-amino)- propyl]-methyl-amide (32)

m/z: 523 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.57-7.45 (m, 2H), 7.27-7.22 (m, 1H), 6.72 (d, J = 13.8 Hz, 1H), 6.58 (s, 1H), 6.12 (s, 1H),5.54 (d, J = 10.5 Hz, 2H), 4.40-4.34 (m, 1H), 4.05-3.93 (m, 2H), 3.82(s, H), 3.69-3.63 (m, 1H), 3.62-3.55 (m, 1H), 3.50 (s, 2H), 3.43-3.28(m, 3H), 3.13 (s, 2H), 2.06-1.94 (m, 1H), 1.85 (s, 3H), 1.53 (s, 3H).7-Methoxy-8-(2-methyl- propenyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3- c]pyrazole-3-carboxylic acidmethyl-[3-(2-oxo-oxazolidin- 3-yl)-propyl]-amide (33)

m/z: 495 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.58-7.45 (m, 2H), 7.27-7.17 (m, 1H), 6.74 (s, 1H), 6.57 (s, 1H), 6.12 (s, 1H), 5.59-5.50 (m,2H), 4.08 (dd, J = 13.5, 6.1 Hz, 1H), 3.82 (s, 3H), 3.67 (dd, J = 13.2,7.7 Hz, 3H), 3.54 (d, J = 5.3 Hz, 1H), 3.20-3.11 (m, 3H), 2.88 (d, J =2.8 Hz, 3H), 1.97 (s, 2H), 1.85 (s, 3H), 1.52 (d, J = 8.4 Hz, 3H).7-Methoxy-8-(2-methyl- propenyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3- c]pyrazole-3-carboxylic acid[2-(acetyl-methyl-amino)- ethyl]-methyl-amide (34)

m/z: 469 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.53-7.43 (m, 2H), 7.24 (d,J = 5.0 Hz, 1H), 6.74 (s, 1H), 6.57 (s, 1H), 6.12 (s, 1H), 5.62 (d, J =1.6 Hz, 2H), 4.33-4.15 (m, 2H), 4.05 (t, J = 9.9 Hz, 2H), 3.82 (s, 3H),3.80-3.66 (m, 2H), 2.14- 1.92 (m, 1H), 1.85 (s, 3H), 1.54 (s, 3H).[7-Methoxy-8-(2-methyl- propenyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3- c]pyrazol-3-yl]-(3-methoxy-d3-pyrrolidin-1-yl)-methanone (49)

m/z: 497 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.53-7.42 (m, 2H), 7.23 (d,J = 5.0 Hz, 1H), 6.73 (s, 1H), 6.58 (s, 1H), 6.12 (s, 1H), 5.56 (s, 2H),4.23-4.14 (m, 1H), 3.99 (dd, J = 17.8, 7.9 Hz, 2H), 3.82 (s, 3H), 3.71(d, J = 9.5 Hz, 1H), 2.22 (dd, J = 13.5, 6.8 Hz, 1H), 1.91 (d, J = 6.6Hz, 2H), 1.85 (s, 3H), 1.71 (dd, J = 12.4, 6.4 Hz, 1H), 1.54 (s, 6H).(2-Methoxy-d3-methyl-2- methyl-pyrrolidin-1-yl)-[7- methoxy-8-(2-methyl-propenyl)-1-thiophen-3-yl-1,4- dihydro-chromeno[4,3-c]pyrazol-3-yl]-methanone (51)

m/z: 512 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.56-7.45 (m, 2H), 7.24 (d,J = 4.7 Hz, 1H), 6.73 (s, 1H), 6.57 (s, 1H), 6.12 (s, 1H), 5.53 (d, J =17.1 Hz, 2H), 4.35 (t, J = 8.0 Hz, 1H), 4.22-4.11 (m, 2H), 3.82 (s, 3H),3.81-3.72 (m, 2H), 3.62-3.53 (m, 2H), 3.42 (t, J = 7.8 Hz, 1H), 1.85 (s,3H), 1.53 (s, 3H). 7-Methoxy-8-(2-methyl-d3-propenyl)-1-thiophen-3-yl-1,4- dihydro-chromeno[4,3-c]pyrazole-3-carboxylic acid methyl-d3-[2-(2-oxo-oxazolidin-3-yl)-ethyl]-amide (56)

m/z: 488 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.52 (s, 1H), 7.46 (s, 1H),7.23 (d, J = 4.8 Hz, 1H), 6.74 (s, 1H), 6.58 (s, 1H), 6.12 (s, 1H), 5.45(s, 2H), 3.83 (s, 3H), 3.78 (s, 2H), 1.85 (s, 3H), 1.55-1.48 (m, 9H).7-Methoxy-8-(2-methyl-d3- propenyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3- c]pyrazole-3-carboxylic acid(2-methoxy-d3-1,1-dimethyl- ethyl)-methyl-amide (58)

m/z: 471 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.56-7.45 (m, 2H), 7.25 (d,J = 4.9 Hz, 1H), 6.96 (s, 1H), 6.69 (s, 1H), 6.57 (s, 1H), 6.11 (s, 1H),5.62 (s, 2H), 3.82 (s, 3H), 3.52 (s, 2H), 1.85 (s, 3H), 1.52 (s, 3H),1.48 (s, 6H). 7-Methoxy-8-(2-methyl- propenyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3- c]pyrazole-3-carboxylic acid(2-methoxy-d3-1,1-dimethyl- ethyl)-amide (59)

m/z: 484 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.98 (s, 1H), 7.59-7.43 (m,2H), 7.24 (d, J = 4.8 Hz, 1H), 6.76-6.66 (m, 1H), 6.57 (s, 1H), 6.12 (s,1H), 5.50 (s, 2H), 4.01-3.87 (m, 1H), 3.82 (s, 3H), 3.62-3.41 (m, 3H),2.02 (s, 3H), 1.85 (s, 3H), 1.52 (s, 3H). 7-Methoxy-8-(2-methyl-propenyl)-1-thiophen-3-yl-1,4- dihydro-chromeno[4,3-c]pyrazole-3-carboxylic acid [2-(acetyl-methyl-d3-amino)- ethyl]-amide(60)

m/z: 515 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.51 (dd, J = 14.6, 7.7 Hz,2H), 7.24 (d, J = 4.9 Hz, 1H), 6.73 (d, J = 5.1 Hz, 1H), 6.57 (s, 1H),6.12 (s, 1H), 5.53 (dd, J = 16.7, 6.7 Hz, 2H), 4.09 (t, J = 6.9 Hz, 1H),3.82 (s, 3H), 3.67 (d, J = 19.2 Hz, 3H), 2.00 (s, 3H), 1.85 (s, 3H),1.56-1.46 (m, 3H). 7-Methoxy-8-(2-methyl- propenyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3- c]pyrazole-3-carboxylic acid[2-(acetyl-methyl-d3-amino)- ethyl]-methyl-d3-amide (61)

m/z: 555 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.54 (dd, J = 29.4, 18.4 Hz,2H), 7.25 (d, J = 4.3 Hz, 1H), 6.87-6.68 (m, 1H), 6.59 (s, 1H), 6.12 (s,1H), 5.62 (s, 1H), 5.53 (d, J = 6.8 Hz, 1H), 4.00-3.92 (m, 1H), 3.80 (s,3H), 3.67-3.59 (m, 1H), 3.55-3.38 (m, 1H), 3.37- 3.23 (m, 2H), 3.07 (dd,J = 16.1, 8.8 Hz, 1H), 2.89 (s, 1H), 2.30 (dd, J = 18.3, 9.1 Hz, 1H),2.19 (d, J = 8.0 Hz, 2H), 2.07-1.70 (m, 6H), 1.48 (s, 3H).7-Methoxy-8-(2-methyl- propenyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3- c]pyrazole-3-carboxylic acid[3-(cyclobutanecarbonyl- methyl-d3-amino)-propyl]- methyl-d3-amide (69)

m/z: 541 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.66 (s, 1H), 7.60-7.53 (m,2H), 7.38 (d, J = 9.2 Hz, 1H), 7.29 (s, 1H), 6.99 (s, 1H), 6.65 (d, J =4.5 Hz, 1H), 5.56 (d, J = 16.4 Hz, 2H), 4.39-4.32 (m, 1H), 4.23- 4.13(m, 2H), 3.91 (s, 3H), 3.83-3.74 (m, 2H), 3.63- 3.53 (m, 2H), 3.49-3.41(m, 1H). 7-Methoxy-8-(1-methyl-d3- 1H-pyrazol-4-yl)-1-thiophen-3-yl-1,4-dihydro- chromeno[4,3-c]pyrazole-3- carboxylic acidmethyl-d3-[2- (2-oxo-oxazolidin-3-yl)-ethyl]- amide (78)

m/z = 503 [M + H]⁺ ¹H NMR (DMSO-d6): δ 7.95 (d, 1H), 7.82 (s, 1H), 7.37-7.28 (m, 1H), 6.66 (d, 1H), 6.47-6.40 (m, 1H), 5.40- 5.32 (m, 2H),4.06-3.98 (m, 1H), 3.76 (s, 3H), 3.63-3.44 (m, 3H), 2.15 (d, 2H), 1.99(d, 1H), 1.82 (d, 2H), 1.62 (septet, 1H), 0.74 (d, 6H).8-Isobutyl-7-methoxy-1- thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3- carboxylic acid [2-(acetyl-methyl-d3-amino)-ethyl]- methyl-d3-amide (82)

m/z = 514 [M + H]⁺ ¹H NMR (DMSO-d6): δ 7.96 (s, 1H), 7.82 (s, 1H), 7.34(s, 1H), 6.66 (d, 1H), 6.44 (d, 1H), 5.35 (s, 2H), 4.23 (s, 1H), 4.06(s, 2H), 3.76 (s, 3H), 3.71-3.59 (d, 2H), 3.50- 3.38 (m, 3H), 2.15 (d,2H), 1.69-1.55 (m, 1H), 0.75 (d, 6H). 8-Isobutyl-7-methoxy-1-thiophen-3-yl-1,4-dihydro- chromeno[4,3-c]pyrazole-3- carboxylic acidmethyl-d3-[2- (2-oxo-oxazolidin-3-yl)-ethyl]- amide (214)

m/z = 490 [M + H]⁺ ¹H NMR (DMSO-d6): δ 7.91 (s, 1H), 7.81 (s, 1H), 7.30(s, 1H), 6.66 (s, 1H), 6.44 (s, 1H), 5.31 (s, 2H), 3.76 (s, 3H), 3.64(s, 2H), 2.13 (d, 2H), 1.69-1.55 (m, 1H), 1.41 (s, 6H), 0.74 (d, 6H).8-Isobutyl-7-methoxy-1- thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3- carboxylic acid (2-methoxy-d3-1,1-dimethyl-ethyl)-methyl- d3-amide (83)

m/z = 517 [M + H]⁺ ¹H NMR (DMSO-d6): δ 8.01-7.92 (m, 1H), 7.82 (s, 1H),7.39-7.29 (m, 1H), 6.66 (s, 1H), 6.47-6.40 (m, 1H), 5.38 (s, 2H), 3.77(s, 4H), 3.50-3.38 (m, 1H), 3.27- 3.17 (m, 1H), 2.15 (d, 2H), 2.01-1.56(m, 6H), 0.74 (d, 6H). 8-Isobutyl-7-methoxy-1-thiophen-3-yl-1,4-dihydro- chromeno[4,3-c]pyrazole-3- carboxylic acid[3-(acetyl- methyl-d3-amino)-propyl]- methyl-d3-amide (84)

m/z: 524 [M + H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 8.42 (s, 1H), 7.98 (s, 1H),7.66-7.53 (m, 2H), 6.95 (s, 1H), 6.88 (s, 1H), 6.69 (dd, J = 10.0, 5.1Hz, 1H), 5.67- 5.56 (m, 2H), 4.36 (t, J = 7.8 Hz, 2H), 4.24-4.13 (m,2H), 3.94 (s, 3H), 3.85-3.74 (m, 2H), 3.63-3.55 (m, 2H).7-Methoxy-8-(1H-pyrazol-4- yl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3- c]pyrazole-3-carboxylic acid methyl-d3-[2-(2-oxo-oxazolidin-3-yl)-ethyl]- amide (85)

m/z = 484 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 8.38 (t, 0.3H), 8.04-7.78 (m,3H), 7.40-7.31 (m, 1H), 6.69- 6.57 (m, 2H), 6.03 (s, 1H), 5.53-5.36 (m,2H), 3.93 (t, 1H), 3.75 (s, 3H), 3.49 (t, 1H), 3.30-3.15 (m, 6H),1.84-1.72 (m, 5H), 1.62 (s, 1H), 1.43 (d, 3H). 7-Methoxy-8-(2-methyl-propenyl)-1-thiophen-3-yl-1,4- dihydro-chromeno[4,3-c]pyrazole-3-carboxylic acid (2-acetylamino-ethyl)-methyl- d3-amide (87)

m/z: 509 [M + H]⁺ ¹H-NMR (400 MHz, CDCl₃) δ 7.66 (s, 1H), 7.58-7.53 (m,2H), 7.38 (s, 1H), 7.28- 7.24 (m, 1H), 6.98 (s, 1H), 6.66 (s, 1H), 5.51(s, 2H), 4.14-4.08 (m, 2H), 3.91 (s, 3H), 3.89-3.85 (m, 2H), 3.51 (s,2H), 1.55 (s, 6H). (3,3-Dimethyl-morpholin-4-yl)-[7-methoxy-8-(1-methyl- d3-1H-pyrazol-4-yl)-1-thiophen-3-yl-1,4-dihydro- chromeno[4,3-c]pyrazol-3-yl]- methanone (96)

m/z = 541 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 7.98 (s, 1H), 7.84-7.80 (m, 1H),7.69 (s, 1H), 7.57 (s, 1H), 7.34 (d, 1H), 6.69-6.59 (m, 1H), 6.03 (s,1H), 5.39 (d, 2H), 4.71 (s, 1H), 4.39 (s, 1H), 4.09 (s, 1 H), 3.76 (s,3H), 3.18 (s, 5H), 2.21 (d, 1H), 1.88-1.19 (m, 6H).7-Methoxy-8-(2-methyl- propenyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3- c]pyrazole-3-carboxylic acidmethyl-d3-((1R,3S)-3-methyl- d3-carbamoyl-cyclohexyl)- amide (107)

m/z = 527 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 8.04 (dd, 1H), 7.90 (dd, 1H),7.39 (dd, 1H), 7.00 (t, 1H), 6.85 (s, 1H), 6.71 (s, 1H), 6.63 (t, 1H),5.81-5.78 (m, 1H), 5.40 (s, 2H), 4.69 (d, 2H), 4.39 (d, 2H), 3.88 (s,2H), 3.84 (s, 3H), 3.59 (s, 3H). 7-Methoxy-8-(1-methyl-1H-pyrrol-3-yl)-1-thiophen-3-yl- 1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylic acid (3-methoxy-d3-methyl-oxetan-3-yl)-methyl-d3-amide (113)

m/z = 528 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 8.02-7.95 (m, 1H), 7.84 (dd, 1H),7.60 (d, 1H), 7.47 (s, 1H), 7.34 (d, 1H), 6.76 (s, 1H), 6.49 (d, 1H),5.44 (s, 2H), 4.70 (d, 2H), 4.40 (d, 2H), 3.88 (s, 2H), 3.84 (s, 3H),3.78 (s, 3H). 7-Methoxy-8-(1-methyl-1H- pyrazol-3-yl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3- c]pyrazole-3-carboxylic acid(3-methoxy-d3-methyl-oxetan- 3-yl)-methyl-d3-amide (114)

m/z = 494 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 8.08-8.00 (m, 1H), 7.90 (dd, 1H),7.39 (d, 1H), 7.00 (s, 1H), 6.85 (s, 1H), 6.71 (s, 1H), 6.63 (t, 1H),5.80 (s, 1H), 5.40 (s, 2H), 4.69 (d, 2H), 4.24 (d, 2H), 3.83 (s, 3H),3.59 (s, 3H), 1.63 (s, 3H). 7-Methoxy-8-(1-methyl-1H-pyrrol-3-yl)-1-thiophen-3-yl- 1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylic acid methyl-d3-(3-methyl-oxetan-3- yl)-amide(115)

m/z = 495 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 7.98 (dd, 1H), 7.84 (dd, 1H),7.60 (d, 1H), 7.47 (s, 1H), 7.34 (dd, 1H), 6.76 (s, 1H), 6.49 (d, 1H),5.43 (s, 2H), 4.69 (d, 2H), 4.24 (d, 2H), 3.84 (s, 3H), 3.78 (s, 3H),1.63 (s, 3H). 7-Methoxy-8-(1-methyl-1H- pyrazol-3-yl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3- c]pyrazole-3-carboxylic acidmethyl-d3-(3-methyl-oxetan-3- yl)-amide (116)

m/z = 495 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 8.00 (dd, 1H), 7.81 (dd, 1H),7.39- 7.34 (m, 2H), 6.87 (s, 1H), 6.60 (s, 1H), 6.01 (d, 1H), 5.49 (s,2H), 4.69 (d, 2H), 4.24 (d, 2H), 3.80 (s, 3H), 3.52 (s, 3H), 1.63 (s,3H). 7-Methoxy-8-(2-methyl-2H- pyrazol-3-yl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3- c]pyrazole-3-carboxylic acidmethyl-d3-(3-methyl-oxetan-3- yl)-amide (118)

m/z = 528 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 8.00 (dd, 1H), 7.81 (dd, 1H),7.39- 7.34 (dd, 2H), 6.87 (s, 1H), 6.60 (s, 1H), 6.01 (d, 1H), 5.49 (s,2H), 4.69 (d, 2H), 4.39 (d, 2H), 3.88 (s, 2H), 3.80 (s, 3H), 3.53 (s,3H). 7-Methoxy-8-(2-methyl-2H- pyrazol-3-yl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3- c]pyrazole-3-carboxylic acid(3-methoxy-d3-methyl-oxetan- 3-yl)-methyl-d3-amide (119)

m/z = 495 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 7.97 (dd, 1H), 7.83 (dd, 1H),7.60 (d, 1H), 7.50 (d, 1H), 7.34 (s, 1H), 6.76 (s, 1H), 6.50 (d, 1H),5.59 (s, 1H), 5.43 (s, 2H), 5.20 (s, 1H), 4.01-3.91 (m, 1H), 3.89-3.54(m, 10H), 2.26-2.17 (m, 1H), 1.95 (s, 1H). 7-Methoxy-8-(1-methyl-1H-pyrazol-3-yl)-1-thiophen-3-yl- 1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylic acid methyl-d3-(tetrahydro-furan-3- yl)-amide(140)

m/z = 511 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 8.06-8.00 (m, 1H), 7.92- 7.87 (m,1H), 7.42-7.36 (m, 1H), 7.00 (t, 1H), 6.88 (s, 1H), 6.71 (s, 1H), 6.64(t, 1H), 5.81 (s, 1H), 5.37 (s, 2H), 5.12-4.86 (m, 1H), 4.46 (s, 1H),3.97-3.79 (m, 3.5H), 3.70-3.50 (m, 4H), 2.47- 2.38 (m, 1H), 2.24-1.98(m, 2H). 7-Methoxy-8-(1-methyl-1H- pyrrol-3-yl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3- c]pyrazole-3-carboxylic acid(3-methoxy-d3-cyclobutyl)- methyl-d3-amide (142)

m/z = 512 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 8.02-7.97 (m, 1H), 7.81 (dd, 1H),7.56 (s, 1H), 7.36 (s, 1H), 7.17 (s, 1H), 6.79-6.69 (m, 1H), 6.63-6.55(m, 1H), 5.58 (s, 1H), 5.42 (s, 2H), 5.19 (s, 1H), 3.99-3.92 (m, 1H),3.81-3.53 (m, 4H), 2.26- 2.14 (m, 1H), 2.03-1.82 (m, 4H). 8-(1-methyl,3-methyl-d3-1H- pyrazol-4-yl)-7-methoxy-1- thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3- carboxylic acid methyl-d3-(tetrahydro-furan-3-yl)-amide (143)

m/z = 494 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 8.03 (dd, 1H), 7.89 (dd, 1H),7.40 (s, 1H), 7.01 (t, 1H), 6.93- 6.84 (m, 1H), 6.71 (s, 1H), 6.64 (t,1H), 5.81 (s, 1H), 5.60 (s, 1H), 5.39 (s, 2H), 5.19 (s, 1H), 3.99-3.92(m, 1H), 3.84 (s, 3H), 3.80-3.53 (m, 7H), 2.26-2.16 (m, 1H), 1.97 (s,1H). 7-Methoxy-8-(1-methyl-1H- pyrrol-3-yl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3- c]pyrazole-3-carboxylic acidmethyl-d3-(tetrahydro-furan-3- yl)-amide (146)

m/z = 504 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 7.96 (dd, 1H), 7.83 (dd, 1H),7.33 (dd, 1H), 6.66 (s, 1H), 6.42 (s, 1H), 5.37 (s, 2H), 4.69 (d, 2H),4.39 (d, 2H), 3.88 (s, 2H), 3.76 (s, 3H), 2.14 (d, 2H), 1.62 (septet,1H), 0.74 (d, 6H). 8-Isobutyl-7-methoxy-1- thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3- carboxylic acid (3-methoxy-d3-methyl-oxetan-3-yl)- methyl-d3-amide (162)

m/z = 471 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 7.96 (dd, 1H), 7.83 (dd, 1H),7.33 (dd, 1H), 6.66 (s, 1H), 6.42 (s, 1H), 5.37 (s, 2H), 4.69 (d, 2H),4.24 (d, 2H), 3.76 (s, 3H), 2.14 (d, 2H), 1.66-1.60 (m, 4H), 0.74 (d,6H). 8-Isobutyl-7-methoxy-1- thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3- carboxylic acid methyl-d3-(3-methyl-oxetan-3-yl)-amide (163)

m/z = 528 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 8.00-7.93 (m, 1H), 7.85- 7.80 (m,1H), 7.60 (d, 1H), 7.33 (d, 1H), 6.76 (s, 1H), 6.50 (d, 1H), 5.76 (s,1H), 5.43 (s, 2H), 4.59-4.41 (m, 4H), 3.99 (s, 1H), 3.84 (s, 3H),3.80-3.76 (m, 3H), 3.69 (s, 1H). 7-Methoxy-8-(1-methyl-1H-pyrazol-3-yl)-1-thiophen-3-yl- 1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylic acid (3-methoxy-d3-oxetan-3-ylmethyl)-methyl-d3-amide (167)

m/z = 527 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 8.06-7.99 (m, 1H), 7.92- 7.87 (m,1H), 7.41-7.36 (m, 1H), 7.00 (s, 1H), 6.94-6.84 (m, 1H), 6.71 (s, 1H),6.63 (t, 1H), 5.80 (s, 1H), 5.40 (s, 2H), 4.58-4.40 (m, 5H), 3.99 (s,1H), 3.84 (s, 3H), 3.59 (s, 3H). 7-Methoxy-8-(1-methyl-1Hpyrrol-3-yl)-1-thiophen-3-yl- 1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylic acid (3-methoxy-d3-oxetan-3-ylmethyl)-methyl-d3-amide (168)

m/z = 526 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 7.96 (s, 1H), 7.83 (s, 1H), 7.60(s, 1H), 7.51 (d, 1H), 7.34 (s, 1H), 6.76 (s, 1H), 6.50 (s, 1H),5.48-5.36 (m, 2H), 5.25 (s, 1H), 4.97 (s, 1H), 3.88- 3.67 (m, 7H), 2.14(s, 1H), 1.85-1.49 (m, 5H). 7-Methoxy-8-(1-methyl-1H-pyrazol-3-yl)-1-thiophen-3-yl- 1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylic acid ((1S,3R)-3-methoxy-d3-cyclopentyl)-methyl-d3-amide (177)

m/z = 525 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 8.02 (s, 1H), 7.90 (s, 1H), 7.39(s, 1H), 7.01 (s, 1H), 6.94-6.84 (m, 1H), 6.71 (s, 1H), 6.64 (s, 1H),5.81 (s, 1H), 5.44-5.32 (m, 2H), 5.24 (s, 1H), 4.97 (s, 1H), 3.87-3.67(m, 4H), 3.59 (s, 3H), 2.13 (s, 1H), 1.87-1.49 (m, 5H).7-Methoxy-8-(1-methyl-1H- pyrrol-3-yl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3- c]pyrazole-3-carboxylic acid((1S,3R)-3-methoxy-d3- cyclopentyl)-methyl-d3-amide (178)

m/z = 523 [M + H]⁺ (2-Methoxy-d3-methyl-2- methyl-pyrrolidin-1-yl)-[7-methoxy-8-(1-methyl-1H- pyrazol-3-yl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3- c]pyrazol-3-yl]-methanone (182)

m/z = 522 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 8.01 (s, 1H), 7.89 (s, 1H), 7.38(s, 1H), 7.00 (s, 1H), 6.85 (s, 1H), 6.71 (s, 1H), 6.63 (s, 1H), 5.80(s, 1H), 5.44 (s, 2H), 4.11-4.02 (m, 1H), 3.90- 3.81 (m, 5H), 3.62-3.54(m, 4H), 2.17-2.07 (m, 1H), 1.88- 1.74 (m, 2H), 1.68-1.59 (m, 1H), 1.42(s, 3H). (2-Methoxy-d3-methyl-2- methyl-pyrrolidin-1-yl)-[7-methoxy-8-(1-methyl-1H- pyrrol-3-yl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3- c]pyrazol-3-yl]-methanone (184)

m/z = 494 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 8.23 (s, 1H), 8.02 (dd, 1H), 7.86(dd, 1H), 7.60 (d, 1H), 7.42 (s, 1H), 7.34 (dd, 1H), 6.76 (s, 1H), 6.49(d, 1H), 5.54 (s, 2H), 5.18 (s, 1H), 3.84 (s, 3H), 3.77 (s, 3H),3.44-3.36 (m, 4H), 1.05 (s, 3H). 7-Methoxy-8-(1-methyl-1H-pyrazol-3-yl)-1-thiophen-3-yl- 1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylic acid methyl-d3-(3-methyl-azetidin- 3-yl)-amide(193)

m/z = 526 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 8.00-7.90 (m, 1H), 7.83 (dd, 1H),7.63-7.46 (m, 2H), 7.32 (dd, 1H), 6.76 (s, 1H), 6.50 (d, 1H), 5.50-5.26(m, 2.5H), 5.02 (s, 0.5H), 3.91-3.75 (m, 7H), 2.02-1.51 (m, 6H).7-Methoxy-8-(1-methyl-1H- pyrazol-3-yl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3- c]pyrazole-3-carboxylic acid((1S,3S)-3-methoxy-d3- cyclopentyl)-methyl-d3-amide (196)

m/z = 525 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 8.00 (s, 1H), 7.89 (dd, 1H), 7.37(d, 1H), 7.00 (d, 1H), 6.89 (d, 1H), 6.71 (s, 1H), 6.64 (t, 1H), 5.81(s, 1H), 5.45-5.24 (m, 2.5H), 5.01 (s, 0.5H), 3.84 (s, 4H), 3.64-3.57(m, 4H), 2.03-1.50 (m, 8H). 7-Methoxy-8-(1-methyl-1H-pyrrol-3-yl)-1-thiophen-3-yl- 1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylic acid ((1S,3S)-3-methoxy-d3-cyclopentyl)-methyl-d3-amide (197)

m/z = 541 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 8.03 (dd, 1H), 7.89 (dd, 1H),7.38 (dd, 1H), 7.00 (t, 1H), 6.86 (s, 1H), 6.72 (s, 1H), 6.63 (t, 1H),5.80 (dd, 1H), 5.37 (s, 2H), 4.09 (d, 1H), 3.85-3.72 (m, 7H), 3.67-3.56(m, 6H). 7-Methoxy-8-(1-methyl-1H- pyrrol-3-yl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3- c]pyrazole-3-carboxylic acid[3-(2-methoxy-d3-ethyl)- oxetan-3-yl]-methyl-d3-amide (198)

m/z = 521 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 7.99 (dd, 1H), 7.85 (dd, 1H),7.33 (dd, 1H), 7.22 (s, 1H), 6.93 (s, 1H), 5.57 (s, 2H), 4.69 (d, 2H),4.24 (d, 2H), 3.90 (s, 3H), 3.45 (septet, 1H), 1.62 (s, 3H), 1.08 (d,6H). 7-Methoxy-8-(propane-2- sulfonyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3- c]pyrazole-3-carboxylic acidmethyl-d3-(3-methyl-oxetan-3- yl)-amide (199)

m/z = 554 [M + H]⁺ ¹H-NMR (DMSO-d6): δ 7.99 (dd, 1H), 7.85 (dd, 1H),7.33 (dd, 1H), 7.22 (s, 1H), 6.94 (s, 1H), 5.57 (s, 2H), 4.69 (d, 2H),4.39 (d, 2H), 3.93-3.85 (m, 5H), 3.45 (septet, 1H), 1.08 (d, 6H).7-Methoxy-8-(propane-2- sulfonyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3- c]pyrazole-3-carboxylic acid(3-methoxy-d3-methyl-oxetan- 3-yl)-methyl-d3-amide (200)

Example 9(8-Isobutyl-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazol-3-yl)-[4-(tetrahydro-furan-2-carbonyl)-[1,4]diazepan-1-yl]-methanone(21)

Step 1

To8-isobutyl-7-methoxy-1-(3-thienyl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylicacid (70.00 mg; 0.18 mmol; 1.00 eq.) in DCM (1.00 ml; 15.60 mmol; 85.68eq.) was added N,N-Diisopropylethylamine (0.04 ml; 0.22 mmol; 1.20 eq.)1-boc-hexahydro-1,4-diazepine (0.04 ml; 0.22 mmol; 1.20 eq.) and2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (0.08ml; 0.27 mmol; 1.50 eq.). After stirring at room temperature for 2 h,the reaction mixture washed with water and 1N HCL. The organic layer wasdried with Na₂SO₄, filtered, concentrated to afford4-(8-Isobutyl-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carbonyl)-[1,4]diazepane-1-carboxylicacid tert-butyl ester (103.00 mg; 0.18 mmol) as a white foam. To4-(8-Isobutyl-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carbonyl)-[1,4]diazepane-1-carboxylicacid tert-butyl ester (103.00 mg; 0.18 mmol) in methanol (1.00 ml; 24.69mmol; 135.58 eq.) was added hydrogen chloride (0.46 ml; 1.82 mmol; 10.00eq.) (4M in dioxane). After stirring for 4 h the reaction was mixturewas concentrated to dryness and diluted with water. Mixture waslyophilized to afford[1,4]Diazepan-1-yl-(8-isobutyl-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazol-3-yl)-methanoneas a white solid.

Step 2

To[1,4]diazepan-1-yl-(8-isobutyl-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazol-3-yl)-methanone(30.00 mg; 0.06 mmol; 1.00 eq.) in DCM (1.00 ml; 15.60 mmol; 242.64 eq.)was added N,N-Diisopropylethylamine (0.01 ml; 0.08 mmol; 1.20 eq.),tetrahydro-2-furoic acid (0.01 ml; 0.13 mmol; 2.00 eq.) and2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (0.03ml; 0.10 mmol; 1.50 eq.). After stirring for 30 min at room temperaturethe reaction was concentrated to dryness and purified by flashchromatography to afford the desired compound (10.7 mg, 30%) as a whitesolid.

¹H NMR (400 MHz, CDCl₃) δ 7.51-7.44 (m, 2H), 7.50-7.44 (m, 1H),7.25-7.21 (m, 1H), 6.59 (d, J=7.0 Hz, 1H), 6.56 (d, J=2.7 Hz, 1H), 5.50(dd, J=4.9, 3.5 Hz, 2H), 4.70-4.58 (m, 1H), 4.53-4.41 (m, 1H), 4.41-4.22(m, 1H), 4.19-4.09 (m, 1H), 4.08-3.82 (m, 4H), 3.79 (s, 3H), 3.71-3.59(m, 2H), 3.58-3.42 (m, 1H), 2.36-2.26 (m, 1H), 2.26-2.20 (m, 2H),2.19-1.83 (m, 3H), 1.78-1.60 (m, 2H), 0.81 (d, J=6.6 Hz, 6H). m/z: 565[M+H]⁺

Example 107-Methoxy-8-(1H-pyrazol-4-yl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid methylamide (22)

Step 1

To8-bromo-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid (100.00 mg; 0.25 mmol; 1.00 eq.) in a microwave vial was added4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrazole-1-carboxylicacid tert-butyl ester (108.35 mg; 0.37 mmol; 1.50 eq.),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(ii), complexwith dichloromethane (1:1) (20.05 mg; 0.02 mmol; 0.10 eq.), and cesiumcarbonate (0.25 ml; 0.49 mmol; 2.00 eq.) (3 Molar solution in water).The vessel was sealed and vacuumed and backfilled with nitrogen (3times). Reaction was microwaved at 100° C. for 30 min. Mixture wasdiluted with EtOAc and washed with water and 1N HCl. Organic layer wasdried (Na₂SO₄), filtered, concentrated to afford8-(1-tert-Butoxycarbonyl-1H-pyrazol-4-yl)-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid as a crude product.

Step 2

To8-(1-tert-Butoxycarbonyl-1H-pyrazol-4-yl)-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid (121.00 mg; 0.24 mmol; 1.00 eq.) in DCM (1.50 ml; 23.40 mmol; 95.64eq.) was added DIPEA (0.09 ml; 0.49 mmol; 2.00 eq.),o-(benzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium tetrafluoroborate(157.13 mg; 0.49 mmol; 2.00 eq.), and n-tert-butylmethylamine (0.06 ml;0.49 mmol; 2.00 eq.). After stirring for 30 min at room temperature themixture was concentrated to dryness and purified by flash chromatographyto afford4-[3-(tert-Butyl-methyl-carbamoyl)-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazol-8-yl]-pyrazole-1-carboxylicacid tert-butyl ester as a white solid (99 mg, 72%).

Step 3

To4-[3-(tert-Butyl-methyl-carbamoyl)-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazol-8-yl]-pyrazole-1-carboxylicacid tert-butyl ester (99.00 mg; 0.18 mmol) in methanol (3.00 ml; 74.06mmol; 302.68 eq.) was added hydrochloric acid (0.20 ml; 0.80 mmol; 3.27eq.) (4M in dioxane). After stirring at room temperature for 1 h, themixture was concentrated and purified by flash chromatography to affordthe desired product (33.8 mg, 34%) as a white solid.

¹H NMR (400 MHz, DMSO) δ 12.83 (s, 1H), 8.33 (dd, J=9.4, 4.6 Hz, 1H),8.07 (dd, J=3.2, 1.4 Hz, 1H), 7.92 (dd, J=5.1, 3.2 Hz, 1H), 7.77 (s,1H), 7.41 (dd, J=5.1, 1.4 Hz, 1H), 7.32 (s, 1H), 6.85 (s, 1H), 6.76 (s,1H), 5.52 (s, 2H), 3.86 (s, 3H), 2.75 (d, J=4.7 Hz, 3H). m/z: 408 [M+H]⁺

Example 11[4-(Azetidine-1-carbonyl)-azepan-1-yl]-(8-isopropoxy-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazol-3-yl)-methanone(26)

To1-(8-isopropoxy-7-methoxy-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carbonyl)azepane-4-carboxylicacid (45.00 mg; 0.09 mmol; 1.00 eq.) in DCM (2.00 ml; 31.20 mmol; 354.72eq.) was added DIPEA (0.02 ml; 0.13 mmol; 1.50 eq.), Azetidine (0.01 ml;0.13 mmol; 1.50 eq.) and2,4,6-tripropyl-[1,3,5,2,4,6]trioxatriphosphinane 2,4,6-trioxide (0.08ml; 0.13 mmol; 1.50 eq.). After stirring at room temperature for 30 minthe reaction mixture was concentrated to dryness and purified by flashchromatography to afford the desired product (24.5 mg, 51%) as a whitesolid.

¹H NMR (400 MHz, CDCl₃) δ 7.54-7.45 (m, 2H), 7.24 (t, J=5.0 Hz, 1H),6.61 (s, 1H), 6.43 (d, J=5.8 Hz, 1H), 5.55-5.41 (m, 2H), 4.59 (d, J=14.3Hz, 1H), 4.23-3.86 (m, 4H), 3.83 (s, 3H), 3.77-3.49 (m, 1H), 3.35-3.27(m, 1H), 2.42-2.07 (m, 4H), 2.03-1.68 (m, 6H), 1.27 (t, J=7.1 Hz, 1H),1.21 (d, J=6.1 Hz, 6H). m/z: 551 [M+H]

Example 128-Isopropoxy-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid (3-amino-propyl)-amide (27)

Step 1

To8-isopropoxy-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid (120.00 mg; 0.31 mmol; 1.00 eq.) in DCM (1.00 ml; 15.60 mmol; 50.24eq.) was added N,N-Diisopropylethylamine (0.07 ml; 0.37 mmol; 1.20 eq.),n-boc-1,3-diaminopropane (81.16 mg; 0.47 mmol; 1.50 eq.) and2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (0.14ml; 0.47 mmol; 1.50 eq.). After stirring for 30 min at room temperature,the reaction mixture was concentrated to dryness and purified by flashchromatography to afford{3-[(8-Isopropoxy-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carbonyl)-amino]-propyl}-carbamicacid tert-butyl ester (170 mg, 100%) as a white solid.

Step 2

To{3-[(8-Isopropoxy-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carbonyl)-amino]-propyl}-carbamicacid tert-butyl ester (172.70 mg; 0.32 mmol) in methanol (4.00 ml; 98.75mmol; 317.98 eq.) was added hydrochloric acid in dioxane (0.31 ml; 1.24mmol; 4.00 eq.). After stirring at room temperature for 18 h thereaction mixture was concentrated to dryness and purified by flashchromatography to afford the desired compound (71.3 mg, 52%) as a whitesolid.

¹H NMR (400 MHz, CDCl₃) δ 8.77-8.64 (m, 2H), 7.55 (d, J=7.2 Hz, 2H),6.62 (s, 1H), 6.36 (s, 1H), 5.51 (s, 2H), 4.13-3.94 (m, 2H), 3.85 (s,3H), 3.65-3.59 (m, 2H), 3.23-3.07 (m, 2H), 2.21-2.09 (m, 1H), 1.21 (d,J=6.0 Hz, 6H). m/z: 443 [M+H]⁺

Example 138-Isopropoxy-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid [3-(cyclobutanecarbonyl-amino)-propyl]-amide (28)

To8-isopropoxy-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid (3-amino-propyl)-amide (27) (65.00 mg; 0.15 mmol; 1.00 eq.) in DCM(1.00 ml; 15.60 mmol; 106.21 eq.) was added N,N-Diisopropylethylamine(0.03 ml; 0.18 mmol; 1.20 eq.) cyclobutanecarboxylic acid (0.14 ml; 1.50mmol; 10.21 eq.) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane2,4,6-trioxide (0.13 ml; 0.22 mmol; 1.50 eq.). After stirring at roomtemperature for 18 h the reaction mixture was concentrated to drynessand purified by flash chromatography to afford the desired compound(55.8 mg, 72%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 7.57-7.46 (m, 2H), 7.23 (d, J=5.0 Hz, 1H),7.16 (t, J=6.3 Hz, 1H), 6.59 (s, 1H), 6.35 (m, 2H), 5.54 (s, 2H), 4.02(dt, J=12.1, 6.0 Hz, 1H), 3.82 (s, 3H), 3.46 (q, J=6.2 Hz, 1H), 3.31 (q,J=6.0 Hz, 2H), 3.03 (p, J=8.6 Hz, 1H), 2.36-2.22 (m, 2H), 2.20-2.10 (m,2H), 2.01-1.80 (m, 2H), 1.79-1.67 (m, 2H), 1.19 (d, J=6.1 Hz, 6H). m/z:525 [M+H]⁺

Example 14 Cyclobutanecarboxylic acid{1-[7-methoxy-8-(2-methyl-propenyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carbonyl]-azepan-4-yl}-amide(37)

To(4-amino-azepan-1-yl)-[7-methoxy-8-(2-methyl-propenyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazol-3-yl]-methanone(55.00 mg; 0.11 mmol; 1.00 eq.) in DCM (1.00 ml; 15.60 mmol; 135.76 eq.)was added N,N-Diisopropylethylamine (0.02 ml; 0.14 mmol; 1.20 eq.)cyclobutanecarboxylic acid (0.14 ml; 1.50 mmol; 13.05 eq.) and2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (0.10ml; 0.17 mmol; 1.50 eq.). After stirring for 30 min at room temperaturethe reaction mixture was washed with NaHCO₃, and extracted with DCM. Theorganic layer was concentrated and purified by flash chromatography toafford the desired compound (60.3 mg, 94%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 7.53-7.44 (m, 2H), 7.23 (dd, J=5.0, 1.3 Hz,1H), 6.76 (s, 1H), 6.57 (s, 1H), 6.12 (s, 1H), 5.60-5.45 (m, 3H),4.61-4.49 (m, 1H), 4.43-4.30 (m, 1H), 4.18-3.99 (m, 2H), 3.82 (s, 3H),3.60-3.48 (m, 1H), 3.45-3.34 (m, 1H), 3.26 (t, J=10.3 Hz, 1H), 3.00-2.81(m, 1H), 2.31-2.06 (m, 4H), 2.01-1.87 (m, 2H), 1.85 (s, 3H), 1.72-1.59(m, 4H), 1.54 (s, 3H). m/z: 547 [M+H]⁺

Example 158-(1,2-Dihydroxy-2-methyl-propyl)-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid tert-butyl-methyl-amide (38)

To7-methoxy-8-(2-methyl-propenyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid tert-butyl-methyl-amide (30.00 mg; 0.07 mmol; 1.00 eq.) in water(0.10 ml), and acetone (0.40 ml) was added 4-methylmorpholine 4-oxide(23.35 mg; 0.20 mmol; 3.00 eq.) and osmium tetroxide (0.51 mg; 0.00mmol; 0.03 eq.). After stirring for 1 h at room temperature the mixturewas quenched with saturated sodium sulfide and extracted with EtOAc. Theorganic layer was dried (Na₂SO₄), filtered, concentrated and purified byflash chromatography to afford the desired compound (22.5 mg, 70%) as awhite solid.

¹H NMR (400 MHz, CDCl₃) δ 7.51 (dd, J=3.2, 1.3 Hz, 1H), 7.47 (dd, J=5.1,3.2 Hz, 1H), 7.21 (dd, J=5.1, 1.3 Hz, 1H), 6.90 (s, 1H), 6.56 (s, 1H),5.53-5.38 (m, 2H), 4.69 (s, 1H), 3.81 (s, 3H), 3.27 (s, 3H), 2.67 (s,1H), 1.52 (s, 9H), 1.28 (dd, J=6.0, 3.0 Hz, 1H), 1.15 (s, 3H), 0.97 (s,3H). m/z: 486 [M+H]⁺

Example 161-[7-Methoxy-8-(2-methyl-propenyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carbonyl]-azepane-4-carboxylicacid dimethylamide (41)

To1-[7-methoxy-8-(2-methyl-propenyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carbonyl]-azepane-4-carboxylicacid (100.00 mg; 0.20 mmol; 1.00 eq.) in DCM (1.00 ml; 15.60 mmol; 79.19eq.) was added N,N-Diisopropylethylamine (0.04 ml; 0.24 mmol; 1.20 eq.),dimethylamine hydrochloride (24.10 mg; 0.30 mmol; 1.50 eq.) and2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (0.17ml; 0.30 mmol; 1.50 eq.). After stirring for 30 min at room temperaturethe reaction mixture was concentrated and purified by flashchromatography to afford the desired compound (92.3 mg, 88%) as a whitesolid.

¹H NMR (500 MHz, cdcl₃) δ 7.46-7.34 (m, 2H), 7.14 (ddd, J=13.8, 4.9, 1.4Hz, 1H), 6.67 (d, J=12.0 Hz, 1H), 6.49 (d, J=1.8 Hz, 1H), 6.03 (s, 1H),5.52-5.41 (m, 2H), 4.61-4.55 (m, 1H), 4.22-4.10 (m, 1H), 3.98-3.85 (m,1H), 3.73 (s, 3H), 3.55-3.48 (m, 1H), 3.45-3.37 (m, 1H), 3.22-3.14 (m,1H), 2.96 (s, 1H), 2.88 (d, J=8.1 Hz, 3H), 2.83 (s, 1H), 2.71-2.60 (m,1H), 2.14-2.04 (m, 1H), 1.95-1.83 (m, 2H), 1.76 (s, 3H), 1.70-1.53 (m,2H), 1.45 (d, J=4.8 Hz, 3H). m/z: 535 [M+H]⁺

Example 171-[7-Methoxy-8-(2-methyl-propenyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carbonyl]-azepane-4-carboxylicacid methylamide (42)

In a similar manner to example 16,1-[7-methoxy-8-(2-methyl-propenyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carbonyl]-azepane-4-carboxylicacid methylamide was obtained from1-[7-Methoxy-8-(2-methyl-propenyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carbonyl]-azepane-4-carboxylicacid (100.00 mg; 0.20 mmol; 1.00 eq.) in DCM (1.00 ml; 15.60 mmol; 79.19eq.), and methylamine hydrochloride (13.30 mg; 0.20 mmol; 1.00 eq.). Thedesired compound was obtained in 52% yield (53.5 mg) as a white solid.

¹H NMR (500 MHz, cdcl₃) δ 7.49-7.43 (m, 2H), 7.21 (d, J=5.1 Hz, 1H),6.74 (s, 1H), 6.56 (s, 1H), 6.10 (s, 1H), 5.55 (t, J=4.9 Hz, 1H), 5.52(t, J=4.1 Hz, 2H), 4.49-4.43 (m, 1H), 4.18 (dt, J=14.5, 5.4 Hz, 1H),4.07-4.00 (m, 1H), 3.95 (dt, J=9.5, 4.4 Hz, 1H), 3.85-3.82 (m, 1H), 3.80(s, 3H), 3.72-3.63 (m, 1H), 3.49-3.42 (m, 1H), 2.78 (dd, J=14.0, 4.8 Hz,3H), 2.34-2.12 (m, 1H), 2.05-1.91 (m, 1H), 1.84 (d, J=1.2 Hz, 3H),1.80-1.68 (m, 2H), 1.54-1.51 (s, 3H). m/z: 521 [M+H]⁺

Example 181-[7-methoxy-8-(2-methyl-propenyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carbonyl]-azepane-4-carboxylicacid amide (43)

To1-[7-methoxy-8-(2-methyl-propenyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carbonyl]-azepane-4-carboxylicacid (75.00 mg; 0.15 mmol; 1.00 eq.) in DMSO (1.00 ml) was added1,1′-carbonylbis(1H-imidazole) (119.72 mg; 0.74 mmol; 5.00 eq.).Reaction was stirred at room temperature for 18 h, then ammonium acetate(34.17 mg; 0.44 mmol; 3.00 eq.) was added and the reaction was continuedto stir at room temperature for 2 h. After completion, water was addedto the mixture and solid formed was filtered, rinsed with water toafford the desired compound (62.5 mg, 84%) as a white solid.

¹H NMR (500 MHz, cdcl₃) δ 7.44-7.34 (m, 2H), 7.15-7.11 (m, 1H), 6.67 (s,1H), 6.49 (s, 1H), 6.03 (s, 1H), 5.47-5.43 (m, 2H), 5.13 (s, 1H), 4.75(s, 1H), 4.44-4.36 (m, 1H), 4.12 (dt, J=14.7, 5.3 Hz, 1H), 4.03-3.95 (m,1H), 3.88 (d, J=14.3 Hz, 1H), 3.83-3.74 (m, 1H), 3.73 (s, 3H), 3.66-3.56(m, 1H), 3.43-3.37 (m, 1H), 2.36-2.25 (m, 1H), 2.23-2.11 (m, 1H),2.03-1.87 (m, 2H), 1.76 (d, J=1.0 Hz, 3H), 1.45 (s, 3H). m/z: 507 [M+H]⁺

Example 197-methoxy-8-(2-methyl-propenyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid [3-(cyclobutanecarbonyl-amino)-propyl]-amide (57)

Step 1

In a similar manner to example 12 step 1,(3-{[7-Methoxy-8-(2-methyl-propenyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carbonyl]-amino}-propyl)-carbamicacid tert-butyl ester was obtained from7-methoxy-8-(2-methyl-propenyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid (150 mg, 0.39 mmol) and N-boc-1,3-diaminopropane (102.5 mg, 0.59mmol, 1.5 eq.).

Step 2

In a similar manner to example 12 step 2,7-methoxy-8-(2-methyl-propenyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid (3-amino-propyl)-amide was obtained from(3-{[7-Methoxy-8-(2-methyl-propenyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carbonyl]-amino}-propyl)-carbamicacid tert-butyl ester and HCl (4M in dioxane).

Step 3

In a similar manner to example 12, step 1,7-methoxy-8-(2-methyl-propenyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid [3-(cyclobutanecarbonyl-amino)-propyl]-amide was obtained from7-Methoxy-8-(2-methyl-propenyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid (3-amino-propyl)-amide (100 mg, 0.23 mmol) andcyclobutanecarboxylic acid (0.14 ml; 1.50 mmol; 6.58 eq.). The desiredcompound was obtained in 97% yield (115 mg) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 7.55 (s, 1H), 7.53-7.48 (m, 1H), 7.25 (d,J=4.7 Hz, 1H), 7.11 (t, J=7.1 Hz, 1H), 6.71 (s, 1H), 6.58 (s, 1H),6.32-6.25 (m, 1H), 6.12 (s, 1H), 5.62 (s, 2H), 3.83 (s, 3H), 3.49 (dd,J=12.3, 5.9 Hz, 2H), 3.34 (dd, J=12.1, 6.0 Hz, 2H), 3.12-3.00 (m, 1H),2.32 (dt, J=19.0, 9.7 Hz, 2H), 2.19 (dd, J=18.8, 9.9 Hz, 2H), 1.98 (dd,J=18.7, 8.5 Hz, 2H), 1.85 (s, 3H), 1.79-1.71 (m, 2H), 1.52 (s, 3H). m/z:521 [M+H]⁺

Example 207-Methoxy-8-(2-methyl-propenyl)-1-thiazol-2-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid tert-butyl-methyl-amide (89) Step 1: 2-Hydrazino-1,3-thiazolehydrochloride

To a mixture of 2-aminothiazole (10.0 g, 100 mmol) and conc.hydrochloric acid (80 mL), was added a solution of sodium nitrite (6.90g, 100 mmol) in water (50 mL) drop wise at −10° C. The reaction mixturewas stirred for 10 min at the same temperature and followed by additionof tin (II)chloride (37.9 g, 200 mmol) in conc. hydrochloric acid (20mL) drop wise carefully so that the temperature of the solution did notexceed −10.deg.C. After the addition, the reaction mixture stirred for30 min at the same temperature. The resulting crystals were collected byfiltration. The crystal was recrystalized from diethylether to affordthe desired compound (11.0 g, 97%) as brown solid.

¹H NMR (400 MHz, DMSO-d₆) δ 10.74 (bs, 1H), 7.27-7.26 (d, J=4.0 Hz, 1H),7.00-6.99 (d, J=4.0 Hz, 1H), 3.45 (bs, 3H). m/z: 116 [M+H]⁺

Step 2: Ethyl8-bromo-7-methoxy-1-(1,3-thiazol-2-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate

To a solution ofethyl-(6-bromo-7-methoxy-4-oxo-2H-chromen-3(4H)-ylidene)(hydroxy)acetate(3.0 g, 0.0084 mol) in a mixture of Ethanol (100 mL) and Acetic acid(100 mL) was added 2-Hydrazino-1,3-thiazole hydrochloride (1.9 g, 0.0126mol) at RT under nitrogen. The reaction mixture was stirred at 100° C.for 4 h. The reaction mixture was concentrated under high vacuum. Theresidue was dissolved with ethyl acetate (40 mL), washed with water (20mL), brine (20 mL), dried over sodium sulphate and concentrated undervacuum. The crude product was purified by column chromatography usingpet ether/ethyl acetate as eluent to afford the desired compound (1.5 g,41%) as pale yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ 8.61 (s, 1H), 7.86-7.85 (d, J=1.4 Hz, 2H),6.86 (s, 1H), 5.45 (s, 2H), 4.37-4.32 (dd, J=7.0, 14.2, 2H), 3.86 (s,3H), 1.34-1.31 (t, J=7.1, 14.2, 3H). m/z: 438 [M+H]⁺

Step 3: Ethyl7-methoxy-8-(2-methylprop-1-en-1-yl)-1-(1,3-thiazol-2-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate

To a solution of ethyl8-bromo-7-methoxy-1-(1,3-thiazol-2yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate(2.6 g, 0.0059 mol) in THF (100 mL) was added2,4,6-Tris-(2-methyl-propenyl)-cyclotriboroxanepyridine complex (2.9 g,0.0089 mol), bis(triphenylphospine)palladium (II) dichloride (417 mg,0.0006 mol) and potassium tri phosphate (2.0 g, 0.0149 mol) at RT undernitrogen. The reaction mixture was degassed with nitrogen for 10 min andwater (10 mL) was added at RT. The reaction mixture was stirred at 90°C. for 12 h. The reaction mixture was filtered through celite and washedwith DCM (50 mL). The filtrate was concentrated under vacuum; crudeproduct was dissolved in DCM (200 mL), washed with water (20 ml), brine(20 mL) and dried over sodium sulphate. The organic solvent was removedunder vacuum; crude product was purified by column chromatography over(60-120) mesh silica gel and pet ether: ethyl acetate as eluent toafford the desired compound (2.2 g, 90%) as a pale yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ 7.94 (s, 1H), 7.87-7.86 (d, J=3.5 Hz, 1H),7.82-7.81 (d, J=3.5 Hz, 1H), 6.69 (s, 1H), 6.01 (s, 1H), 5.42 (s, 2H),4.35-4.33 (d, J=7.1 Hz, 2H), 3.77 (s, 3H), 1.82 (s, 3H), 1.70 (s, 3H),1.34-1.31 (t, J=7.1, 14.2 Hz, 3H). m/z: 412 [M+H]

Step 4:7-Methoxy-8-(2-methylprop-1-en-1-yl)-1-(1,3-thiazol-2-yl)-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid

To a solution of ethyl7-methoxy-8-(2-methylprop-1-en-1-yl)-1-(1,3-thiazol-2-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate(1 g, 0.0024 mol) in mixture of THF (35 mL), H₂O (10 mL), MeOH (5 mL)was added LiOH.H₂O (302 mg, 0.0073 mol) at RT. The reaction mixture wasstirred at RT for 4 h. The reaction mixture was evaporated and acidifiedwith 1.5N HCl solution. The separated solid was filtered and dried underhigh vacuum to afford the desired compound (900 mg, 97%) as an off-whitesolid.

¹H NMR (400 MHz, DMSO-d₆) δ 13.57 (bs, 1H), 8.00 (s, 1H), 7.85-7.84 (d,J=3.5 Hz, 1H), 7.80 (d, J=3.5 Hz, 1H), 6.69 (s, 1H), 6.11 (s, 1H), 5.41(s, 2H), 3.77 (s, 3H), 1.83 (s, 3H), 1.71 (s, 3H). m/z: 384 [M+H]⁺

Step 5:7-Methoxy-8-(2-methyl-propenyl)-1-thiazol-2-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid tert-butyl-methyl-amide

To a solution of7-Methoxy-8-(2-methylprop-1-en-1-yl)-1-(1,3-thiazol-2-yl)-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid (900 mg, 0.0023 mol) in DCM (50 mL) was added N-tert-butyl methylamine (225 mg, 0.0028 mol), HATU (1.1 g, 0.0028 mol) and diisopropylethyl amine (0.6 mL, 0.0035 mol) at RT under nitrogen. The reactionmixture was stirred at RT for 16 h. The reaction mixture was quenched tosodium bicarbonate (10 mL, 10%), extracted with DCM (2×50 mL). Thecombined organic layer was washed with NaHCO₃ solution (1×100 mL, 10%solution), brine (100 mL) and dried over anhydrous sodium sulphate. Thesolvent was removed under vacuum; the crude product was purified bycolumn chromatography using pet ether and ethyl acetate (9:1) as eluentto afford the desired compound (850 mg, 80%) as an off-white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 8.14 (s, 1H), 7.79-7.76 (dd, J=3.5, 6.3 Hz,2H), 6.70 (s, 1H), 6.12 (s, 1H), 5.25 (s, 2H), 3.77 (s, 3H), 3.12 (s,3H), 1.84 (s, 3H), 1.74 (s, 3H), 1.44 (s, 9H). m/z: 453 [M+H]⁺

Example 217-Methoxy-8-(2-methyl-propenyl)-1-thiophen-2-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid tert-butyl-methyl-amide (90) Step 1: tert-Butyl1-(2-thienyl)hydrazinecarboxylate

To a solution of 2-Bromo thiophene (10 g, 0.0613 mol) in DMSO (200 mL)was added tert-butyl carbazate (16.3 g, 0.1227 mol), cesium carbonate(40 g, 0.1227 mol) followed by CuI (1.2 g, 0.0061 mol) and4-Hydroxy-L-Proline (1.6 g, 0.0123 mol) at RT under nitrogen. Thereaction mixture was stirred at 80° C. for 14 h. The reaction mixturewas cooled to RT, quenched with water (100 mL) and extracted with ethylacetate (3×200 mL). The combined organic layer was washed with water(100 mL×2), brine (100 mL), dried over sodium sulphate and evaporatedunder vacuum. The crude product was purified by column chromatography byusing pet ether and ethyl acetate (7:3) as eluent to afford the desiredcompound (3.0 g, 40%) as a brown liquid.

¹H NMR (400 MHz, DMSO-d₆) δ 6.89-6.87 (dd, J=1.7, 5.4 Hz, 1H), 6.81-6.79(dd, J=3.4, 7.2 Hz, 2H), 5.38 (s, 2H), 1.49 (s, 9H). m/z: 115 [M+H]⁺

Step 2: 2-Thienylhydrazine hydrochloride

To a stirred solution of tert-butyl 1-(2-thienyl)hydrazinecarboxylate(4.3 g, 0.0201 mol) in dichloromethane (20 mL) was added HCl in dioxane(30 mL) at RT under nitrogen. The reaction mixture was stirred at RT for8 h. The organic solvent was removed under reduced pressure to affordthe desired compound (2.9 g, 96%) as pale brown solid.

¹H NMR (400 MHz, DMSO-d₆) δ 10.17 (bs, 3H), 8.41 (bs, 1H), 7.07-7.05(dd, J=1.4, 5.4 Hz, 1H), 6.85-6.83 (dd, J=3.6, 5.4 Hz, 1H), 6.72-6.71(dd, J=1.4, 3.7 Hz, 1H). m/z: 115 [M+H]⁺

Step 3: Ethyl8-bromo-7-methoxy-1-(2-thienyl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate

To a solution ofethyl-(6-bromo-7-methoxy-4-oxo-2H-chromen-3(4H)-ylidene)(hydroxy)acetate(6.0 g, 0.0168 mol) in a mixture of Ethanol (100 mL) and acetic acid(100 mL) was added 2-thienylhydrazine hydrochloride (2.9 g, 0.0252 mol)at RT under nitrogen. The reaction mixture was stirred at 100° C. for 4h. The reaction mixture was concentrated under high vacuum. The residuewas dissolved with ethyl acetate (40 mL), washed with water (20 mL),brine (20 mL), dried over sodium sulphate and concentrated under vacuum.The crude product was purified by column chromatography using petether/ethyl acetate as eluent to afford desired compound (4.0 g, 55%) asa pale yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ 7.84-7.82 (dd, J=1.2, 5.5 Hz, 1H), 7.49-7.47(dd, J=1.2, 3.6 Hz, 1H), 7.24-7.22 (dd, J=3.8, 5.4 Hz, 1H), 6.83 (s,1H), 6.72 (s, 1H), 5.51 (s, 2H), 4.33-4.28 (dd, J=7.1, 14.2 Hz. 2H),3.82 (s, 3H), 1.32-1.28 (t, J=7.1, 14.2 Hz, 3H). m/z: 437 [M+H]

Step 4:7-Methoxy-8-(2-methyl-propenyl)-1-thiophen-2-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid ethyl ester

To a solution of Ethyl8-bromo-7-methoxy-1-(2-thienyl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate(3.8 g, 0.0087 mol) in THF (100 mL) was added2,4,6-Tris-(2-methyl-propenyl)-cyclotriboroxanepyridine complex (4.3 g,0.0131 mol), bis(triphenylphospine)palladium (II) dichloride (306 mg,0.0004 mol) and potassium tri phosphate (2.4 g, 0.0174 mol) at RT undernitrogen. The reaction mixture was degassed with nitrogen for 10 min andwater (10 mL) was added at RT. The reaction mixture was stirred at 90°C. for 12 h. The reaction mixture was filtered through celite and washedwith DCM (50 mL). The filtrate was concentrated under vacuum; the crudeproduct was dissolved in DCM (200 mL), washed with water (20 ml), brine(20 mL) and dried over sodium sulphate. The organic solvent was removedunder vacuum; crude product was purified by column chromatography usingpet ether: ethyl acetate as eluent to afford the desired compound (2.5g, 70%) as pale yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ 7.79-7.77 (dd, J=1.4, 5.5 Hz, 1H), 7.46-7.45(dd, J=1.5, 3.7 Hz, 1H), 7.20-7.18 (dd, J=3.7, 5.6 Hz, 1H), 6.66 (s,1H), 6.56 (s, 1H), 6.00 (s, 1H), 5.47 (s, 2H), 4.33-4.27 (dd, J=7.1,14.2 Hz, 2H), 3.74 (s, 3H), 1.73 (d, J=1.1 Hz, 3H), 1.39 (d, J=1.2 Hz,3H), 1.32-1.28 (t, J=7.1, 14.2 Hz, 3H). m/z: 411 [M+H]⁺

Step 5:7-Methoxy-8-(2-methyl-propenyl)-1-thiophen-2-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid

To a solution of7-methoxy-8-(2-methyl-propenyl)-1-thiophen-2-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid ethyl ester (1 g, 0.0024 mol) in mixture of THF (35 mL), H₂O (10mL), MeOH (5 mL) was added LiOH.H₂O (303 mg, 0.0073 mol) at RT. Thereaction mixture was stirred at RT for 4 h. The reaction mixture wasevaporated and acidified with 1.5N HCl solution. The separated solid wasfiltered and dried under high vacuum to afford the desired compound (800mg, 75%) as an off-white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 13.30 (bs, 1H), 7.78-7.76 (dd, J=1.4, 5.6Hz, 1H), 7.45-7.44 (dd, J=1.4, 3.7 Hz, 1H), 7.19-7.17 (dd, J=3.7, 5.5Hz, 1H), 6.66 (s, 1H), 6.56 (s, 1H), 6.00 (s, 1H), 5.46 (s, 2H), 3.73(s, 3H), 1.73 (s, 3H), 1.39 (s, 3H). m/z: 383 [M+H]⁺

Step 6:7-Methoxy-8-(2-methyl-propenyl)-1-thiophen-2-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid tert-butyl-methyl-amide

To a solution of7-methoxy-8-(2-methyl-propenyl)-1-thiophen-2-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid (800 mg, 0.0021 mol) in DCM (50 mL) was added N-tert-butylmethylamine (220 mg, 0.0025 mol), HATU (950 mg, 0.0025 mol) anddiisopropylethylamine (0.6 mL, 0.0032 mol) at RT under nitrogen. Thereaction mixture was stirred at RT for 16 h. The reaction mixture wasquenched to sodium bicarbonate (10 mL, 10%), extracted with DCM (2×50mL). The combined organic layer was washed with NaHCO₃ solution (1×100mL, 10% solution), brine (100 mL) and dried over anhydrous sodiumsulphate. The solvent was removed under vacuum; the crude product waspurified by column chromatography using pet ether and ethyl acetate(9:1) as eluent to afford the desired compound (850 mg, 90%) as a whitesolid.

¹H NMR (400 MHz, DMSO-d₆) δ 7.75-7.73 (dd, J=1.4, 5.5 Hz, 1H), 7.42-7.41(dd, J=1.4, 3.6 Hz, 1H), 7.18-7.15 (dd, J=3.8, 5.6 Hz, 1H), 6.66 (s,1H), 6.59 (s, 1H), 6.01 (s, 1H), 5.33 (s, 2H), 3.73 (s, 3H), 3.12 (s,3H) 1.73 (s, 3H), 1.41 (s, 12H). m/z: 452 [M+H]⁺

Example 228-Isobutyl-7-methoxy-1-thiophen-2-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid tert-butyl-methyl-amide (91) Step 1:8-Isobutyl-7-methoxy-1-thiophen-2-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid ethyl ester

To a solution of7-methoxy-8-(2-methyl-propenyl)-1-thiophen-2-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid ethyl ester (1.2 g, 0.0027 mol) in methanol and ethyl acetatemixture (100 mL) was added palladium on carbon (20%, 0.24 g). Thereaction mixture was hydrogenated under 3 bar of pressure for 8 h at RT.The reaction mixture was filtered through celite to remove the catalystand the filtrate was concentrated under vacuum. The residue was purifiedby column chromatography using pet ether/ethyl acetate as eluent toafford the desired compound (1.1 g, 90%) as an off white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 7.81-7.79 (dd, J=1.4, 5.5 Hz, 1H), 7.43-7.41(dd, J=1.4, 3.7 Hz, 1H), 7.20-7.18 (dd, J=3.7, 5.5 Hz, 1H), 6.65 (s,1H), 6.36 (s, 1H), 5.44 (s, 2H), 4.33-4.27 (dd, J=7.0, 14.2 Hz, 2H),3.74 (s, 3H), 2.12-2.10 (d, J=6.9 Hz, 2H), 1.59-1.56 (m, 1H), 1.32-1.28(t, J=7.1, 14.2 Hz, 3H), 0.86-0.85 (d, J=6.6 Hz, 6H).

Step 2:8-Isobutyl-7-methoxy-1-thiophen-2-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid

To a solution of8-isobutyl-7-methoxy-1-thiophen-2-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid ethyl ester (1.1 g, 0.0027 mol) in mixture of THF (35 mL), H₂O (10mL), MeOH (5 mL) was added LiOH.H₂O (332 mg, 0.0080 mol) at RT. Thereaction mixture was stirred at RT for 4 h. The reaction mixture wasevaporated and acidified with 1.5N HCl solution. The separated solid outwas filtered to afford the desired compound (900 mg, 88%) as anoff-white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 13.33 (bs, 1H), 7.79-7.78 (dd, J=1.4, 5.5Hz, 1H), 7.41-7.40 (dd, J=1.4, 3.7 Hz, 1H), 7.19-7.17 (dd, J=3.8, 5.5Hz, 1H), 6.65 (s, 1H), 6.36 (s, 1H), 5.43 (s, 2H), 3.73 (s, 3H),2.12-2.10 (d, J=7.0 Hz, 2H), 1.59-1.56 (m, 1H), 0.71-0.70 (d, J=6.6 Hz6H) m/z: 385 [M+H]⁺

Step 3:8-Isobutyl-7-methoxy-1-thiophen-2-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid tert-butyl-methyl-amide

To a solution of8-isobutyl-7-methoxy-1-thiophen-2-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid (900 mg, 0.0023 mol) in DCM (50 mL) was added N-tert-butyl methylamine (245 mg, 0.0028 mol), HATU (1.0 g, 0.0028 mol) and diisopropylethyl amine (0.6 mL, 0.0038 mol) at RT under nitrogen. The reactionmixture was stirred at RT for 16 h. The reaction mixture was quenched tosodium bicarbonate (10 mL, 10%), extracted with DCM (2×50 mL). Thecombined organic layer was washed with NaHCO₃ solution (100 mL, 10%solution), brine (100 mL) and dried over anhydrous sodium sulphate. Thesolvent was removed under vacuum; the crude product was purified bycolumn chromatography using pet ether and ethyl acetate (9:1) as eluentto afford the desired compound (800 mg, 75%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 7.76-7.75 (dd, J=1.4, 5.5 Hz, 1H), 7.38-7.37(dd, J=1.4, 3.7 Hz, 1H), 7.18-7.15 (dd, J=3.7, 5.6 Hz, 1H), 6.64 (s,1H), 6.39 (s, 1H), 5.30 (s, 2H), 3.73 (s, 3H), 3.12 (s, 3H), 3.12 (s,3H), 2.12-2.10 (d, J=7.0 Hz, 2H), 1.60-1.56 (m, 1H), 1.41 (s, 9H)0.71-0.70 (d, J=6.6 Hz 6H). m/z: 454 [M+H]⁺

Example 23(3,3-Dimethyl-morpholin-4-yl)-(8-isobutylsulfanyl-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazol-3-yl)-methanone(97) Step 1:8-Isobutylsulfanyl-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid

To8-bromo-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid (100.00 mg; 0.25 mmol; 1.00 eq.) suspended in [1,4]Dioxane (3.00ml) was added 2-Methyl-propane-1-thiol (33.22 mg; 0.37 mmol; 1.50 eq.),palladium acetate (2.76 mg; 0.01 mmol; 0.05 eq.),4,5-Bis-diphenylphosphanyl-9,9-dimethyl-9H-xanthene (14.21 mg; 0.02mmol; 0.10 eq.), and potassium carbonate (101.81 mg; 0.74 mmol; 3.00eq.). The reaction was heated at 120° C. for 8 days. Mixture was dilutedwith EtOAc and washed with brine. The organic layer was dried (Na₂SO₄),filtered, concentrated to afford product8-Isobutylsulfanyl-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid as a yellow crude product.

Step 2:(3,3-Dimethyl-morpholin-4-yl)-(8-isobutylsulfanyl-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazol-3-yl)-methanone

To8-isobutylsulfanyl-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid (80.00 mg; 0.19 mmol; 1.00 eq.) suspended in DCM (3.00 ml; 46.80mmol; 243.67 eq.) was added2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (0.17ml; 0.29 mmol; 1.50 eq.), 3,3-Dimethyl-morpholine (0.14 ml; 0.29 mmol;1.50 eq.) and Ethyl-diisopropyl-amine (0.10 ml; 0.58 mmol; 3.00 eq.).The reaction was stirred at RT for 1 h. Mixture was concentrated andpurified by flash chromatography to afford the desired product (40 mg,40%) as a white solid.

¹H-NMR (DMSO-d6): δ 8.02-7.98 (s, 1H), 7.88-7.83 (m, 1H), 7.35 (dd, 1H),6.72 (s, 1H), 6.60 (s, 1H), 5.37 (s, 2H), 3.94 (m, 2H), 3.80 (s, 3H),3.72 (t, 2H), 3.42 (s, 2H), 2.34 (d, 2H), 1.60 (septet, 1H), 1.42 (s,6H), 0.91 (d, 6H). m/z=514 [M+H]⁺

Example 248-isopropylsulfanyl-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid tert-butyl-methyl-amide (52)

In a similar manner to example 23,8-isopropylsulfanyl-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid tert-butyl-methyl-amide was obtained from8-Isopropylsulfanyl-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid (170 mg, 0.42 mmol), and n-tert-butylmethylamine (73.63 mg, 0.84mmol, 2 eq.) as a white solid in 15% yield (29 mg). m/z=472 [M+H]⁺, HPLCretention time=6.45 min.

Example 257-methoxy-8-(propane-2-sulfonyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid tert-butyl-methyl-amide (79)

To8-isopropylsulfanyl-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid tert-butyl-methyl-amide (24 mg, 0.05 mmol) in DCM (2 mL) was added3-chloroperbenzoic acid (11.40 mg; 0.05 mmol; 1.00 eq.). The reactionwas stirred at RT for 2 h. The mixture was purified by flashchromatography to afford the desired product (8 mg, 32%) as a whitesolid. m/z=504 [M+H]⁺, HPLC retention time=4.40 min.

Example 268-Cyclopropanesulfonyl-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazol-3-yl)-(3,3-dimethyl-morpholin-4-yl)-methanone(106

Step 1:8-(cyclopropylsulfonyl)-7-methoxy-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylicacid

To8-Bromo-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid (100.00 mg; 0.25 mmol; 1.00 eq.) suspended inN,N-Dimethyl-formamide (3.00 ml) was added cyclopropanesulfinic acidsodium (47.19 mg; 0.37 mmol; 1.50 eq.), copper iodide (23.38 mg; 0.12mmol; 0.50 eq.), and N,N′-Dimethyl-ethane-1,2-diamine (0.04 ml; 0.37mmol; 1.50 eq.). The reaction mixture was heated to 90° C. for 18 h. Themixture was filtered, concentrated and lyophilized to afford8-(cyclopropylsulfonyl)-7-methoxy-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylicacid as a blue crude solid.

Step 2:(8-Cyclopropanesulfonyl-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazol-3-yl)-(3,3-dimethyl-morpholin-4-yl)-methanone

In a similar manner to example 23 above step 2,(8-cyclopropanesulfonyl-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazol-3-yl)-(3,3-dimethyl-morpholin-4-yl)-methanonewas obtained from8-(cyclopropylsulfonyl)-7-methoxy-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylicacid (30.00 mg; 0.07 mmol; 1.00 eq.) and 3,3-dimethyl-morpholine (0.05ml; 0.10 mmol; 1.50 eq.). The desired compound was obtained in a yieldof 12 mg (33%) as a blue solid.

LCMS: m/z=530 [M+H]⁺ HPLC retention time=3.24 min.

Example 27(3,3-Dimethyl-morpholin-4-yl)-[7-methoxy-8-(propane-2-sulfonyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazol-3-yl]-methanone(112)

Step 1:7-methoxy-8-(propane-2-sulfonyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid

In a similar manner to example 26 (step 1),7-methoxy-8-(propane-2-sulfonyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid was obtained from8-bromo-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid (100.00 mg; 0.25 mmol; 1.00 eq.) and propane-2-sulfinic acid sodium(47.94 mg; 0.37 mmol; 1.50 eq.) as a crude blue solid.

Step 2:(3,3-Dimethyl-morpholin-4-yl)-[7-methoxy-8-(propane-2-sulfonyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazol-3-yl]-methanone

In a similar manner to example 26 (step 2),(3,3-Dimethyl-morpholin-4-yl)-[7-methoxy-8-(propane-2-sulfonyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazol-3-yl]-methanonewas obtained from7-Methoxy-8-(propane-2-sulfonyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid (100.00 mg; 0.23 mmol; 1.00 eq.), and 3,3-Dimethyl-morpholine (0.17ml; 0.35 mmol; 1.50 eq.) in 8.2% yield (10 mg) as a blue solid. LCMS:m/z=532 [M+H]⁺, HPLC retention time=3.25 min.

Example 28(3,3-Dimethyl-morpholin-4-yl)-[7-methoxy-8-(2-methyl-propane-1-sulfonyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazol-3-yl]-methanone(127)

Step 1:7-Methoxy-8-(2-methyl-propane-1-sulfonyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid

In a similar manner to example 26 (step 1),7-Methoxy-8-(2-methyl-propane-1-sulfonyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid was obtained from8-Bromo-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid (100.00 mg; 0.25 mmol; 1.00 eq.) and 2-Methyl-propane-1-sulfinicacid sodium (53.10 mg; 0.37 mmol; 1.50 eq.) as a blue crude solid.

Step 2:(3,3-Dimethyl-morpholin-4-yl)-[7-methoxy-8-(2-methyl-propane-1-sulfonyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazol-3-yl]-methanone

In a similar manner to example 26 (step 2),(3,3-Dimethyl-morpholin-4-yl)-[7-methoxy-8-(2-methyl-propane-1-sulfonyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazol-3-yl]-methanonewas obtained from7-Methoxy-8-(2-methyl-propane-1-sulfonyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid (30.00 mg; 0.07 mmol; 1.00 eq.), and 3,3-Dimethyl-morpholine (46.22mg; 0.40 mmol; 6.00 eq.) as a white solid in 13.7% yield (5 mg).

LCMS: m/z=546 [M+H]⁺, HPLC retention time=3.56 min.

Example 297-Methoxy-8-(propane-2-sulfonyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid (3-hydroxymethyl-oxetan-3-yl)-amide (187)

In a similar manner to example 27,7-methoxy-8-(propane-2-sulfonyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid (3-hydroxymethyl-oxetan-3-yl)-amide was obtained from7-Methoxy-8-(propane-2-sulfonyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid (70.00 mg; 0.16 mmol; 1.00 eq.) and (3-Amino-oxetan-3-yl)-methanol(24.92 mg; 0.24 mmol; 1.50 eq.) as white solid in 25% yield (21 mg).

¹H-NMR (DMSO-d6): δ 8.77 (s, 1H), 8.02 (dd, 1H), 7.86 (dd, 1H), 7.34(dd, 1H), 7.19 (s, 1H), 6.93 (s, 1H), 5.64 (s, 2H), 5.14 (s, 1H), 4.67(d, 2H), 4.51 (d, 2H), 3.90 (s, 3H), 3.68 (d, 2H), 3.45 (septet, 1H),1.08 (d, 6H). m/z=520 [M+H]⁺

Example 307-Methoxy-8-(propane-2-sulfonyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid (3-methyl-oxetan-3-yl)-amide (188)

In a similar manner to example 27,7-methoxy-8-(propane-2-sulfonyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid (3-methyl-oxetan-3-yl)-amide was obtained from7-Methoxy-8-(propane-2-sulfonyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid (70.00 mg; 0.16 mmol; 1.00 eq.) and 3-Methyl-oxetan-3-ylaminehydrochloride (29.87 mg; 0.24 mmol; 1.50 eq.) as a white solid in 34%yield (28 mg).

¹H-NMR (DMSO-d6): δ 8.95 (s, 1H), 8.03 (dd, 1H), 7.85 (dd, 1H), 7.34(dd, 1H), 7.18 (s, 1H), 6.93 (s, 1H), 5.64 (s, 2H), 4.71 (d, 2H), 4.31(d, 2H), 3.90 (s, 3H), 3.45 (septet, 1H), 1.59 (s, 3H), 1.07 (d, 6H).m/z=504 [M+H]⁺

Example 31(3,3-Dimethyl-morpholin-4-yl)-[8-(1-hydroxy-2-methyl-propyl)-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazol-3-yl]-methanone(131)

To(3,3-dimethyl-morpholin-4-yl)-[7-methoxy-8-(2-methyl-propenyl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazol-3-yl]-methanone(70.00 mg; 0.15 mmol; 1.00 eq.) suspended in THF (3.00 ml), was addedmethylsulfanylmethane; with borane (16.63 mg; 0.22 mmol; 1.50 eq.). Thereaction was stirred at RT for 2 h. Then NaOH (2N solution) was addedvery slowly. The reaction mixture was purified using reverse phaseprep-HPLC (45-60% CH₃CN in 0.1% NH₄OH in H₂O) to afford the desiredproduct (19 mg, 26%) as a white solid.

¹H-NMR (DMSO-d6): δ 7.86 (dd, 1H), 7.78 (dd, 1H), 7.28 (dd, 1H), 6.92(s, 1H), 6.65 (s, 1H), 5.39 (d, 1H), 5.26 (d, 1H), 4.56 (d, 1H), 4.50(t, 1H), 4.03-3.96 (m, 1H), 3.93-3.85 (m, 1H), 3.77-3.70 (m, 5H), 3.42(s, 2H), 1.61 (sextet, 1H), 1.42 (d, 6H), 0.74 (d, 3H), 0.68 (d, 3H).m/z=498 [M+H]⁺

Example 32(3,3-Dimethyl-morpholin-4-yl)-[7-methoxy-1-thiophen-3-yl-8-(5-trimethylsilanyl-5H-[1,2,4]triazol-3-yl)-1,4-dihydro-chromeno[4,3-c]pyrazol-3-yl]-methanone(139)

To diazomethyl-trimethyl-silane (0.17 ml; 0.33 mmol; 3.00 eq.) suspendedin Ethoxy-ethane (3.00 ml) at 0° C. was added n-butyl lithium (0.09 ml;0.22 mmol; 2.00 eq.). The reaction mixture was stirred at 0° C. for 30min then3-(3,3-Dimethyl-morpholine-4-carbonyl)-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-8-carbonitrile(50.00 mg; 0.11 mmol; 1.00 eq.) was added and the reaction was stirredat 0° C. for another 30 min. The reaction mixture was warmed to RT andstirred at RT for 1 h. The mixture was concentrated and purified bycolumn chromatography to afford the desired product (18 mg, 29%) as awhite solid.

¹H-NMR (DMSO-d6): δ 7.92 (dd, 1H), 7.72 (dd, 1H), 7.28 (dd, 1H), 6.79(s, 1H), 6.73 (s, 1H), 5.43 (s, 2H), 3.96-3.92 (m, 2H), 3.74-3.68 (m,5H), 3.42 (s, 2H), 3.18 (s, 1H), 1.43 (s, 6H), 0.06 (s, 9H). m/z=565[M+H]⁺

Example 33(3,3-Dimethyl-morpholin-4-yl)-[7-methoxy-1-thiophen-3-yl-8-(5H-[1,2,4]triazol-3-yl)-1,4-dihydro-chromeno[4,3-c]pyrazol-3-yl]-methanone(161)

To(3,3-dimethyl-morpholin-4-yl)-[7-methoxy-1-thiophen-3-yl-8-(5-trimethylsilanyl-5H-[1,2,4]triazol-3-yl)-1,4-dihydro-chromeno[4,3-c]pyrazol-3-yl]-methanone(34.00 mg; 0.06 mmol; 1.00 eq.) dissolved in THF (3.00 ml) was addedtetrabutyl-ammonium fluoride (1M in THF) (0.30 ml; 0.30 mmol; 5.00 eq.)and the reaction was stirred at RT for 18 h. Reaction mixture wasconcentrated and purified by reverse phase prep-HPLC (35-40% CH₃CN in0.1% NH₄OH in H₂O) to afford the desired product (36 mg, 82%) as a whitesolid.

¹H-NMR (DMSO-d6) (tetrabutyl ammonium salt): δ 7.89 (dd, 1H), 7.79 (dd,1H), 7.73 (s, 1H), 7.53 (s, 1H), 7.31 (dd, 1H), 6.70 (s, 1H), 5.31 (s,2H), 3.96 (t, 2H), 3.83 (s, 3H), 3.73 (t, 2H), 3.43 (s, 2H), 3.20-3.13(m, 9H), 1.64-1.52 (m, 9H), 1.43 (s, 6H), 1.33 (sextet, 9H), 0.94 (t,12H). m/z=493 [M+H]⁺

Example 34(8-Aminomethyl-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazol-3-yl)-(3,3-dimethyl-morpholin-4-yl)-methanone(166)

Step 1: Ethyl8-cyano-7-methoxy-1-(3-thienyl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate

To a solution of ethyl8-bromo-7-methoxy-1-(3-thienyl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxylate(2 g, 0.0459 mol) in NMP (50 mL), was added CuI (90 mg, 0.5 mmol) andfollowed by CuCN (825 mg, 9.1 mmol) in a sealed tube. The reactionmixture was heated to 160° C. for 16 h. The reaction mixture wasfiltered through celite and the filtrate was concentrated. The crudeproduct was purified by column chromatography by usingdichloromethane/methanol (9:1) as eluent. The product was trituratedwith acetonitrile and filtered, to afford of the desired compound (0.7g, 83%) as a white solid.

¹H NMR (400 MHz, DMSO) δ 8.05-8.04 (dd, J=1.4, 3.1 Hz, 1H), 7.90-7.88(dd, J=3.2, 5.1 Hz, 1H), 7.37-7.35 (dd, J=1.4, 5.1 Hz, 1H), 5.63 (s,1H), 4.33-4.28 (m, 2H), 3.89 (s, 1H), 1.32-1.28 (t, J=12.9 Hz, 3H).m/z=382 [M+H]⁺

Step 2:8-Cyano-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid

To8-cyano-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid ethyl ester (300.00 mg; 0.79 mmol; 1.00 eq.) dissolved in Methanol(6.00 ml; 177.52 mmol; 225.69 eq.) was added potassium hydroxide (66.20mg; 1.18 mmol; 1.50 eq.) and water (0.60 ml). The reaction mixture washeated to 50° C. for 2 h. The reaction was concentrated and lyophilizedto afford the crude desired product as a gray solid.

Step 3:3-(3,3-Dimethyl-morpholine-4-carbonyl)-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-8-carbonitrile(86)

To8-cyano-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid (270.00 mg; 0.76 mmol; 1.00 eq.) suspended in DCM (6.00 ml; 93.60mmol; 122.50 eq.) was added2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (1.35ml; 2.29 mmol; 3.00 eq.), 3,3-Dimethyl-morpholine (176.01 mg; 1.53 mmol;2.00 eq.) and ethyl-diisopropyl-amine (0.38 ml; 2.29 mmol; 3.00 eq.).The reaction was stirred at RT for 1 h. Mixture was concentrated andpurified by flash chromatography to afford the desired product (309 mg,90%) as a white solid. LCMS: m/z=451 [M+H]⁺

Step 4:(8-Aminomethyl-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazol-3-yl)-(3,3-dimethyl-morpholin-4-yl)-methanone

3-(3,3-dimethyl-morpholine-4-carbonyl)-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-8-carbonitrile(50.00 mg; 0.11 mmol; 1.00 eq.) was dissolved in amonia in methanol(10.00 ml; 20.00 mmol; 180.20 eq.) and the reaction mixture was runthrough an H-cube under full H₂ pressure using Raney nickel cartridge at70° C. for 2 h. The mixture was concentrated and purified by reversephase prep-HPLC (35-45% CH₃CN in 0.1% NH₄OH in H₂O) to afford thedesired product as white solid (7 mg, 14%). LCMS: m/z=455 [M+H]⁺, HPLCretention time=2.71 min.

Example 35N-[3-(3,3-Dimethyl-morpholine-4-carbonyl)-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazol-8-ylmethyl]-acetamide(175)

To(8-aminomethyl-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazol-3-yl)-(3,3-dimethyl-morpholin-4-yl)-methanone(20.00 mg; 0.04 mmol; 1.00 eq.) suspended in DCM (2.00 ml; 31.20 mmol;709.11 eq.) was added 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane2,4,6-trioxide (0.04 ml; 0.07 mmol; 1.50 eq.), acetic acid (3.96 mg;0.07 mmol; 1.50 eq.) and ethyl-diisopropyl-amine (0.02 ml; 0.13 mmol;3.00 eq.). The reaction mixture was stirred at RT for 1 h. The mixturewas concentrated and purified by reverse phase prep-HPLC (32-38% CH₃CNin 0.1% NH₄OH in H₂O) to afford the desired product (4 mg, 18%) as awhite solid.

¹H-NMR (DMSO-d6): δ 7.91-7.76 (m, 2H), 7.28-7.22 (m, 1H), 6.74-6.61 (m,2H), 5.37-5.26 (m, 2H), 4.14 (s, 0.5H), 3.96 (d, 3.5H), 3.84-3.69 (m,5H), 3.42 (s, 2H), 2.05 (s, 0.5H), 1.91 (s, 0.5H), 1.86-1.76 (m, 3H),1.42 (s, 6H). m/z=497 [M+H]⁺

Example 368-Cyano-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid tert-butyl-methyl-amide (12)

To8-bromo-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid tert-butyl-methyl-amide (210 mg, 0.44 mmol) in NMP (5 mL) was addedCuCN 43.5 mg, 0.48 mmol, 1.1 eq.) and CuI (8.4 mg, 0.044 mmol 0.1 eq.).The reaction was microwaved at 170° C. for 70 min. The mixture waspurified by reverse phase prep HPLC to afford the desired product (10mg, 5%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 7.54 (ddd, J=4.7, 4.1, 2.4 Hz, 2H), 7.19 (dd,J=5.0, 1.5 Hz, 1H), 6.97 (s, 1H), 6.62 (s, 1H), 5.58 (s, 2H), 3.92 (s,3H), 3.28 (s, 3H), 1.53 (s, 9H). m/z=423 [M+H]⁺

Example 377-methoxy-8-(1-methyl-1H-pyrrol-3-yl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide (179)

To8-bromo-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid (3-methyl-oxetan-3-yl)-amide (1.00 g; 2.10 mmol; 1.00 eq.) wasadded1-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrole(652.08 mg; 3.15 mmol; 1.50 eq.), palladium acetate (23.57 mg; 0.10mmol; 0.05 eq.), dicyclohexyl-(2′,6′-dimethoxy-biphenyl-2-yl)-phosphane(86.18 mg; 0.21 mmol; 0.10 eq.), potassium carbonate (870.42 mg; 6.30mmol; 3.00 eq.), dioxane (10.00 ml) and water (1.00 ml). The reactionmixture was heated at 120° C. for 24 h. The mixture was concentrated,filtered and purified by reverse phase prep-HPLC (35-45% CH₃CN in 0.1%NH₄OH in H₂O) to afford the hydrolyzed product (14 mg, 1.3%) as a whitesolid.

¹H-NMR (DMSO-d6): δ 8.06 (s, 1H), 7.90 (s, 1H), 7.39 (s, 1H), 7.31 (s,1H), 7.00 (s, 1H), 6.79 (s, 1H), 6.71 (s, 1H), 6.63 (s, 1H), 5.77 (s,1H), 5.49 (s, 2H), 4.95 (s, 2H), 3.83 (s, 3H), 3.65-3.56 (m, 5H),3.53-3.45 (m, 2H), 1.30 (s, 3H). m/z=495 [M+H]

Example 387-Methoxy-8-(1-methyl-1H-pyrazol-3-yl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide (185)

Using a procedure similar to example 37,7-methoxy-8-(1-methyl-1H-pyrazol-3-yl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide was obtained from8-Bromo-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid (3-methyl-oxetan-3-yl)-amide (1.00 g; 2.10 mmol; 1.00 eq.) and1-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(655.19 mg; 3.15 mmol; 1.50 eq.), as a white solid in 2% yield (20 mg).

¹H-NMR (DMSO-d6): δ 8.01 (s, 1H), 7.85 (d, 1H), 7.60 (s, 1H), 7.41 (s,1H), 7.32 (s, 2H), 6.76 (s, 1H), 6.49 (s, 1H), 5.53 (s, 2H), 4.95 (s,2H), 3.84 (s, 3H), 3.78 (s, 3H), 3.66-3.57 (m, 2H), 3.53-3.45 (m, 2H),1.30 (s, 3H). m/z=496 [M+H]⁺

Example 397-Methoxy-8-(tetrahydro-furan-3-yl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid tert-butyl-methyl-amide (194)

To8-(2,5-dihydro-furan-3-yl)-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid tert-butyl-methyl-amide (30.00 mg; 0.06 mmol; 1.00 eq.) suspendedin acetic acid (3.00 ml) was added palladium on carbon (0.02 ml; 0.32mmol; 5.00 eq.). The flask was capped with a rubber septum and toppedwith a hydrogen balloon. The reaction mixture was stirred at RT for 18h. Triethylamine was added, the mixture was filtered through celite andthe mixture was purified by reverse phase prep-HPLC (55-63% CH₃CN in0.1% NH₄OH in H₂O) to afford the desired product (11 mg, 37%) as a whitesolid.

¹H-NMR (DMSO-d6): δ 7.95 (dd, 1H), 7.84 (dd, 1H), 7.32 (dd, 1H), 6.69(s, 1H), 6.60 (s, 1H), 5.34 (d, 2H), 3.85 (t, 1H), 3.79 (s, 3H),3.71-3.57 (m, 2H), 3.43 (quintet, 1H), 3.21-3.15 (m, 4H), 2.10-2.00 (m,1H), 1.56-1.40 (m, 10H). m/z=468 [M+H]⁺

Example 407-Methoxy-8-(tetrahydro-furan-2-yl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid tert-butyl-methyl-amide (201)

In a similar manner to example 39,7-methoxy-8-(tetrahydro-furan-2-yl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid tert-butyl-methyl-amide was obtained from8-(4,5-Dihydro-furan-2-yl)-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid tert-butyl-methyl-amide (65.00 mg; 0.14 mmol; 1.00 eq.) as a whitesolid in 9% yield (6 mg).

¹H-NMR (DMSO-d6): δ 7.93 (dd, 1H), 7.82 (dd, 1H), 7.30 (dd, 1H), 6.75(s, 1H), 6.66 (s, 1H), 5.33 (q, 2H), 4.90 (dd, 1H), 3.77 (s, 3H),3.65-3.58 (m, 2H), 3.17 (s, 3H), 2.18-2.07 (m, 1H), 1.85-1.74 (m, 1H),1.70-1.59 (m, 1H), 1.50-1.40 (m, 10H). m/z=468 [M+H]⁺

Example 417-Methoxy-8-(1-methyl-1H-pyrazol-3-yl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid (1S,3S)-3-amino-cyclopentyl ester (180)

Step 1

To8-bromo-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid (500.00 mg; 1.23 mmol; 1.00 eq.) suspended in DCM (10.00 ml; 156.01mmol; 127.06 eq.) was added (1S,3S)-3-amino-cyclopentanol hydrochloride(253.43 mg; 1.84 mmol; 1.50 eq.),[(benzotriazol-1-yloxy)-dimethylamino-methylene]-dimethyl-ammoniumtetrafluoroborate (788.43 mg; 2.46 mmol; 2.00 eq.), andethyl-diisopropyl-amine (0.61 ml; 3.68 mmol; 3.00 eq.). The reaction wasstirred at RT for 1 h. The mixture was concentrated and purified byflash chromatography to afford a mixture of8-bromo-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid ((1S,3S)-3-hydroxy-cyclopentyl)-amide and8-bromo-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid (1S,3S)-3-amino-cyclopentyl ester (total 247 mg, 41%) as a whitesolid.

Step 2

To a mixture of8-bromo-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid ((1S,3S)-3-hydroxy-cyclopentyl)-amide and8-bromo-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid (1S,3S)-3-amino-cyclopentyl ester (120.00 mg; 0.24 mmol; 1.00 eq.)was added1-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(76.37 mg; 0.37 mmol; 1.50 eq.), palladium acetate (2.75 mg; 0.01 mmol;0.05 eq.), dicyclohexyl-(2′,6′-dimethoxy-biphenyl-2-yl)-phosphane (10.05mg; 0.02 mmol; 0.10 eq.), potassium carbonate (101.46 mg; 0.73 mmol;3.00 eq.), dioxane (4.00 ml) and water (0.40 ml). The reaction mixturewas heated at 140° C. for 18 h. The mixture was concentrated and aportion of it was purified by flash chromatography (KPNH, 80-100%EtOAc/Hexanes, 0-20% MeOH/EtOAc) to afford7-methoxy-8-(1-methyl-1H-pyrazol-3-yl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid ((1S,3S)-3-hydroxy-cyclopentyl)-amide (78 mg, 65%) as a whitesolid. The rest of the crude material was purified by reverse phaseprep-HPLC (35-45% CH₃CN in 0.1% NH₄OH in H₂O) to afford7-methoxy-8-(1-methyl-1H-pyrazol-3-yl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid (1S,3S)-3-amino-cyclopentyl ester (5 mg, 4.2%) as a white solid.

¹H-NMR (DMSO-d6): δ 7.94 (s, 1H), 7.82 (s, 1H), 7.60 (s, 1H), 7.50 (s,1H), 7.33 (s, 1H), 6.77 (s, 1H), 6.50 (s, 1H), 5.38 (s, 2H), 4.96 (s,1H), 3.85 (s, 3H), 3.78 (s, 3H), 3.63 (s, 1H), 1.32 (d, 12H). m/z=492[M+H]⁺

Example 427-Methoxy-8-(1-methyl-1H-pyrrol-3-yl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid (1S,3S)-3-amino-cyclopentyl ester (181)

In a similar manner to example 41,7-methoxy-8-(1-methyl-1H-pyrrol-3-yl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid (1S,3S)-3-amino-cyclopentyl ester was obtained from8-bromo-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid (1S,3S)-3-amino-cyclopentyl ester, in 3% yield (3 mg) as a whitesolid.

¹H-NMR (DMSO-d6): δ 8.01 (s, 1H), 7.88 (s, 1H), 7.38 (s, 1H), 7.01 (s,1H), 6.88 (s, 1H), 6.72 (s, 1H), 6.64 (s, 1H), 5.81 (s, 1H), 5.34 (s,2H), 4.98 (s, 1H), 4.09 (s, 5H), 3.84 (s, 3H), 3.59 (s, 4H), 1.48-1.14(m, 12H). m/z=491 [M+H]⁺

Example 437-Methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid tert-butyl-methyl-amide (133)

To8-bromo-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid tert-butyl-methyl-amide (70.00 mg; 0.15 mmol; 1.00 eq.), was addedboronic acid,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(ii), complexwith dichloromethane (1:1) (24.00 mg; 0.03 mmol; 0.20 eq.), cesiumcarbonate (143.63 mg; 0.44 mmol; 3.00 eq.) dioxane (2.00 ml; 23.47 mmol;159.74 eq.) and water (0.20 ml). The reaction was heated to 120° C. for18 h. The reaction mixture was concentrated, purified by reverse phaseusing prep-HPLC (45-55% CH₃CN in 0.1% NH₄OH in H₂O) to afford7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid tert-butyl-methyl-amide as the major product as a white solid (30mg, 51%).

¹H-NMR (DMSO-d6): δ 7.94 (dd, 1H), 7.81 (dd, 1H), 7.32 (dd, 1H), 6.67(d, 1H), 6.62 (d, 1H), 6.47 (dd, 1H), 5.33 (s, 2H), 3.73 (s, 3H), 3.17(s, 3H), 1.44 (s, 9H). m/z=398 [M+H]⁺

Example 44(2-Methoxymethyl-2-methyl-pyrrolidin-1-yl)-(7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazol-3-yl)-methanone(183)

In a similar manner to example 43,(2-methoxymethyl-2-methyl-pyrrolidin-1-yl)-(7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazol-3-yl)-methanonewas obtained from(2-Hydroxymethyl-2-methyl-pyrrolidin-1-yl)-(7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazol-3-yl)-methanoneas a white solid (13 mg, 50%).

¹H-NMR (DMSO-d6): δ 7.95 (s, 1H), 7.82 (s, 1H), 7.32 (s, 1H), 6.69-6.60(m, 2H), 6.49-6.44 (m, 1H), 5.43 (s, 2H), 4.05 (s, 1H), 3.90-3.79 (m,2H), 3.73 (s, 3H), 3.59-3.52 (m, 1H), 2.16-2.07 (m, 1H), 1.88-1.72 (m,2H), 1.68-1.58 (m, 1H), 1.42 (s, 3H). m/z=443 [M+H]⁺

Example 45(3,3-Dimethyl-morpholin-4-yl)-(7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazol-3-yl)-methanone(128)

In a similar manner to example 43,(3,3-Dimethyl-morpholin-4-yl)-(7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazol-3-yl)-methanonewas obtained from(8-Bromo-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazol-3-yl)-(3,3-dimethyl-morpholin-4-yl)-methanoneas a white solid (13 mg, 46%).

LCMS: m/z=427 [M+H]⁺, HPLC retention time=3.65 min.

Example 467-Methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3,8-dicarboxylicacid 8-amide 3-(tert-butyl-methyl-amide) (50) Step 1:8-Carbamoyl-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid

To8-cyano-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid (45.00 mg; 0.13 mmol; 1.00 eq.) (example 34) in DMSO (4 mL) wasadded H₂O₂ (0.12 ml; 1.27 mmol; 10.00 eq.) and 2.0M NaOH aq (0.64 ml;1.27 mmol; 10.00 eq.). The reaction was stirred at RT for 2 h. Themixture was purified by reverse phase HPLC to afford the desired product(17 mg, 35%) as a white solid.

Step 2:7-Methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3,8-dicarboxylicacid 8-amide 3-(tert-butyl-methyl-amide)

To8-carbamoyl-7-methoxy-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid (17 mg, 0.05 mmol) in DCM (1.00 ml; 46.80 mmol; 1022.39 eq.) wasadded DIPEA (0.02 ml; 0.09 mmol; 2.00 eq.),o-(benzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium tetrafluoroborate(29.40 mg; 0.09 mmol; 2.00 eq.), and N-tert-butylmethylamine (0.01 ml;0.09 mmol; 2.00 eq.). Reaction was stirred at RT for 30 min. The mixturewas concentrated and purified by reverse phase prepHPLC to afford thedesired product (2.5 mg, 11%) as a white solid.

¹H NMR (400 MHz, MeOD) δ 7.88 (s, 1H), 7.71 (s, 1H), 7.69-7.56 (m, 1H),7.26 (d, J=4.9 Hz, 1H), 6.79 (s, 1H), 5.46 (s, 2H), 3.98 (s, 3H), 3.23(s, 3H), 1.54 (s, 9H). m/z=441 [M+H]⁺

Example 47

The following compounds were prepared using procedures analogous tothose disclosed in Example 1:

Boronic acid Amine Starting Starting Compound material material LC/MSNMR

m/z: 532 [M + H]⁺ ¹H NMR (DMSO- d6): δ 8.03 (dd, 1H), 7.91 (dd, 1H),7.82 (s, 1H), 7.38 (d, 1H), 7.21 (s, 1H), 6.79 (d, 2H), 5.40 (s, 2H),3.96 (t, 2H), 3.86 (s, 3H), 3.73 (t, 3H), 3.42 (s, 2H), 1.42 (s, 6H),1.05-0.93 (m, 4H). (8-(1-cyclopropyl-1H-pyrazol-4-yl)-7-methoxy-1-(thiophen-3-yl)- 1,4-dihydrochromeno[4,3-c]pyrazol-3-yl)(3,3- dimethylmorpholino)methanone (215)

m/z: 547 [M + H]⁺ ¹H NMR (DMSO- d6): δ 7.96 (s, 1H), 7.83 (s, 1H), 7.60(s, 1H), 7.46 (s, 1H), 7.35-7.30 (m, 1H), 6.76 (s, 1H), 6.49 (s, 1H),5.41 (s, 2H), 4.27 (t, 1H), 4.19 (t, 1H), 3.84 (s, 3H), 3.77 (s, 3H),3.65-3.57 (m, 3H), 3.44 (t, 1H), 2.00 (d, 3H), 1.49 (d, 6H).1-(4-(7-methoxy-8-(1-methyl-1H- pyrazol-3-yl)-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3- c]pyrazole-3-carbonyl)-3,3-dimethylpiperazin-1-yl)ethanone (216)

m/z: 492 [M + H]⁺ HPLC re- tention time: 4.91 min(7-methoxy-8-(1-methyl-1H- pyrazol-3-yl)-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3- c]pyrazol-3-yl)(3- methylmorpholino)methanone(218)

Example 48N-(1,3-dihydroxy-2-methylpropan-2-yl)-7-methoxy-N-methyl-8-(1-methyl-1H-pyrazol-3-yl)-1-(thiophen-3-yl)-1,4-dihydrochromeno[4,3-c]pyrazole-3-carboxamide(217)

Compound 116 (MSC2501240) (30.00 mg; 0.06 mmol; 1.00 eq.) was dissolvedin hydrochloric acid in water (2.00 ml). The reaction mixture wasstirred at room temperature overnight. The mixture was applied to aprep-HPLC (32-38% CH₃CN in 0.1% NH₄OH in H₂O) to afford the desiredproduct7-Methoxy-8-(1-methyl-1H-pyrazol-3-yl)-1-thiophen-3-yl-1,4-dihydro-chromeno[4,3-c]pyrazole-3-carboxylicacid (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-methyl-amide (19.00 mg;0.04 mmol) as a white solid (61%). LCMS: m/z=513 [M+H]⁺, HPLC retentiontime: 2.67 min.

Example 49 EC₅₀ of Cyclic AMP Production in CHO FSHR Cells+EC₂₀ FSH(Assay A)

2500 Cho-FSHR-LUC-1-1-43 cells were plated per well in 5 μl of phenolred free DMEM/F12+1% FBS. Cells were plated in 384 well, solid white lowvolume plates (Greiner 784075) by Multidrop. Cells were assayed byadding 100 μl of 2× EC₂₀ FSH/IBMX in DMEM/F12+0.1% BSA) by Multidrop to2 μl of test compound stamped in 384 well plates (compounds are diluted1:50). The final FSH concentration was 0.265 μM, and the final IBMXconcentration was 200 μM. The compound plate map was as follows: Column1: 2 μl of DMSO; Column 2: 2 μl of DMSO; Columns 3-12 and 13-24: 2 μl oftest compound, diluted 1:4 in 100% DMSO, or 2 μl of FSH, diluted 1:4 inDMEM/F12+0.1% BSA. The starting concentration for FSH was 50 nM (finalconcentration was 0.5 nM). Furthermore, Column 23 contained 2 μl ofEC₁₀₀ FSH reference (100×) (diluted in DMEM/F12+0.1% BSA) at a finalconcentration of 0.5 nM, and Column 24 contained 2 μl of 1 mM AS707664/2reference compound 2. 5 μl of compound+EC₂₀ FSH mixture were transferredto cell plates (1:2 dilution into 5 μl of cell media) The plates wereincubated at 37° C. for 1 h. 10 μl of mixed HTRF (CisBio #62AM4PEC)reagents were added per well and incubated at room temperature for 1 h.The plates were read on Envision using the cAMP HTRF—low volume 384 wellprotocol. The readout was the calculated fluorescence ratio (665 nm/620nm). Values given in percent (%) indicate the percental effect(response) at a certain concentration of agonist relative to the maximumresponse of the FSH standard. The results are provided below.

Example 50 Rat Granulosa EC₅₀ FSH (Assay B)

The assay was performed pursuant to the teaching of Yanofsky et al.(2006) Allosteric activation of the follicle-stimulating hormone (FSH)receptor by selective, nonpeptide agonists (JBC 281(19): 13226-13233,which is incorporated by reference in the disclosure of the invention).The results are provided below.

The data is interpreted according to the following:

+ >5 μM; ++ >1-5 μM; +++ >0.1-1 μM; ++++ <0.1 μM. Compound number AssayA Assay B 1 ++++ ++++ 2 ++++ 54% @ 30 μM 3 ++++ ++ 4 +++ 62% @ 6 μM 5++++ ++ 6 ++++ ++ 7 ++ 43.5% @ 6 μM 8 + 9 ++ 40.5% @ 30 μM 10 +++ ++ 11++ 12 ++++ ++ 13 +++ ++ 14 ++ 15 + 16 + 17 +++ + 18 ++ 30% @ 30 μM 19++++ ++ 20 +++ +++ 21 +++ + 22 ++ 23 ++++ ++++ 24 ++++ ++ 25 + 26 ++ +27 + 28 + + 29 ++++ 30 +++ 31 ++++ 32 +++ 33 +++ 34 ++++ 35 ++ 36 +++ 37++ 38 ++ 39 ++++ 40 ++++ 41 +++ 42 +++ 43 ++++ 44 +++ 45 +++ 46 ++ 47 ++48 ++++ 49 +++ 50 ++++ +++ 51 ++++ 52 ++++ +++ 53 ++++ 54 +++ 55 ++++ 56++++ 57 ++ 58 ++++ 59 +++ 60 +++ 61 ++++ 62 +++ 63 ++++ +++ 64 ++++ 65++++ 66 ++++ 67 ++++ 68 ++++ 69 +++ 70 ++++ 71 ++++ 72 ++++ 73 ++++ 74++++ 75 ++++ 76 ++++ 77 ++++ 78 ++++ 79 ++++ + 80 ++++ 81 ++++ 82 ++++++ 83 ++++ +++ 84 + 85 ++++ 86 ++++ 87 +++ 88 ++++ 89 ++++ 90 ++++ 91++++ ++ 92 ++++ 93 ++++ +++ 94 ++++ +++ 95 ++++ +++ 96 ++++ +++ 97 ++++++ 98 ++++ ++ 99 +++ +++ 100 +++ 101 ++++ 102 +++ 103 +++ 104 ++ 105++++ ++++ 106 +++ 107 + 108 ++++ ++ 109 +++ 110 ++++ 111 +++ 112 ++ 113++++ +++ 114 ++++ ++ 115 ++++ +++ 116 ++++ ++ 117 +++ 118 ++++ 119 ++++++ 120 ++++ 121 ++++ + 122 ++++ + 123 ++++ 124 ++++ 125 ++++ ++ 126 +++++++ 127 + 128 + 129 ++++ 130 ++++ 131 ++++ ++ 132 ++++ +++ 133 ++ 134+++ 135 ++ 136 + 137 ++ 138 + 139 ++++ ++ 140 ++ 141 ++ 142 + 143 +++144 ++++ 145 +++ 146 +++ +++ 147 ++++ +++ 148 ++++ +++ 149 ++++ +++ 150++++ +++ 151 ++++ +++ 152 ++++ 153 ++++ ++++ 154 ++++ ++ 155 + 156 +++157 +++ +++ 158 ++ 159 ++++ ++++ 160 ++++ ++++ 161 ++++ ++++ 162 +++++++ 163 ++++ +++ 164 ++ 165 + 166 ++ 167 +++ +++ 168 ++++ +++ 169 +++++++ 170 ++++ ++ 171 +++ 172 + 173 + 174 +++ 175 +++ + 176 ++++ 177 ++178 ++ 179 +++ 180 ++++ 181 ++++ 182 ++++ ++++ 183 +++ 184 ++++ ++++ 185+++ 186 ++++ +++ 187 + 188 + 189 ++++ ++++ 190 ++++ 191 ++++ 192 ++++193 + 194 ++++ +++ 195 ++++ 196 + 197 ++ 198 ++++ ++++ 199 ++++ 200++++ + 201 +++ ++ 202 +++ +++ 203 +++ 204 ++++ 205 ++++ ++++ 206 +++ 207++++ 208 ++++ ++++ 209 ++++ ++++ 210 ++++ + 211 ++++ ++++ 212 ++++ 213++++ 214 ++++ ++ 215 ++++ +++ 216 ++++ 217 ++ 218 ++++ +++

Example 51 Pharmaceutical Preparations

(A) Injection vials: A solution of 100 g of an active ingredientaccording to the invention and 5 g of disodium hydrogen phosphate in 3 lof bidistilled water is adjusted to pH 6.5 using 2 N hydrochloric acid,sterile filtered, transferred into injection vials, is lyophilized understerile conditions and is sealed under sterile conditions. Eachinjection vial contains 5 mg of active ingredient.

(B) Suppositories: A mixture of 20 g of an active ingredient accordingto the invention is melted with 100 g of soy lecithin and 1400 g ofcocoa butter, is poured into moulds and is allowed to cool. Eachsuppository contains 20 mg of active ingredient.

(C) Solution: A solution is prepared from 1 g of an active ingredientaccording to the invention, 9.38 g of NaH₂PO₄.2H₂O, 28.48 g ofNa₂HPO₄.12H₂O and 0.1 g of benzalkonium chloride in 940 ml ofbidistilled water. The pH is adjusted to 6.8, and the solution is madeup to 1 l and sterilized by irradiation. This solution could be used inthe form of eye drops.

(D) Ointment: 500 mg of an active ingredient according to the inventionis mixed with 99.5 g of Vaseline under aseptic conditions.

(E) Tablets: A mixture of 1 kg of an active ingredient according to theinvention, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and0.1 kg of magnesium stearate is pressed to give tablets in aconventional manner in such a way that each tablet contains 10 mg ofactive ingredient.

(F) Coated tablets: Tablets are pressed analogously to Example E andsubsequently are coated in a conventional manner with a coating ofsucrose, potato starch, talc, tragacanth and dye.

(G) Capsules: 2 kg of an active ingredient according to the inventionare introduced into hard gelatin capsules in a conventional manner insuch a way that each capsule contains 20 mg of the active ingredient.

(H) Ampoules: A solution of 1 kg of an active ingredient according tothe invention in 60 l of bidistilled water is sterile filtered,transferred into ampoules, is lyophilized under sterile conditions andis sealed under sterile conditions. Each ampoule contains 10 mg ofactive ingredient.

(I) Inhalation spray: 14 g of an active ingredient according to theinvention are dissolved in 10 l of isotonic NaCl solution, and thesolution is transferred into commercially available spray containerswith a pump mechanism. The solution could be sprayed into the mouth ornose. One spray shot (about 0.1 ml) corresponds to a dose of about 0.14mg.

While a number of embodiments of this invention are described herein, itis apparent that the basic examples may be altered to provide otherembodiments that utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by t appended claims rather than by the specific embodimentsthat have been represented by way of example.

We claim:
 1. A compound of formula I-c,

or a pharmaceutically acceptable salt thereof, wherein: Z is N; each Ris independently hydrogen, C₁₋₆ aliphatic, C₃₋₁₀ aryl, a 3-8 memberedsaturated or partially unsaturated carbocyclic ring, a 3-7 memberedheterocylic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur; each of which is optionally substituted; or two Rgroups on the same atom are taken together with the atom to which theyare attached to form a C₃₋₁₀ aryl, a 3-8 membered saturated or partiallyunsaturated carbocyclic ring, a 3-7 membered heterocylic ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, ora 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; each of whichis optionally substituted; R¹ is —OR, R² is —R, halogen, -haloalkyl,—OR, —SR, —CN, —NO₂, —SO₂R, —SOR, —C(O)R, —CO₂R, —C(O)N(R)₂, —NRC(O)R,—NRC(O)N(R)₂, —NRSO₂R, or —N(R)₂; R³ is a 5-6 membered monocyclicheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur; which is optionally substituted; R⁵ is C₁₋₆aliphatic, C₃₋₁₀ aryl, a 3-8 membered saturated or partially unsaturatedcarbocyclic ring, a 3-7 membered heterocylic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or a 5-6membered monocyclic heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur; each of which is optionallysubstituted; R⁶ is hydrogen, C₁₋₆ aliphatic, C₃₋₁₀ aryl, a 3-8 memberedsaturated or partially unsaturated carbocyclic ring, a 3-7 memberedheterocylic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur; each of which is optionally substituted; or R⁵ andR⁶, together with the atom to which each is attached, form a 3-8membered heterocylic ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, or a 3-8 membered heteroaryl ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur; each of which is optionally substituted; and p is 0 or
 1. 2. Thecompound of claim 1, wherein R¹ is —OR, and R is C₁₋₆ aliphatic.
 3. Thecompound of claim 1, wherein R² is hydrogen, Br, CN,


4. The compound of claim 3, wherein R² is


5. The compound of claim 3, wherein R² is


6. The compound of claim 1, wherein R³ is


7. The compound of claim 1, wherein R⁵ is methyl, t-butyl, —CD₃,


8. The compound of claim 7, wherein R⁵ is t-butyl, and R⁶ is anoptionally substituted C₁₋₆ aliphatic.
 9. The compound of claim 1,wherein Z is N and the ring formed by Z, R⁵ and R⁶ is


10. The compound of claim 9, wherein Z is N and the ring formed by Z, R⁵and R⁶ is


11. The compound of claim 1, wherein R⁶ is hydrogen, methyl, t-butyl, or—CD₃.
 12. The compound of claim 1, of formula I-f:

or a pharmaceutically acceptable salt thereof.
 13. The compound of claim12, wherein R² is 5-6 membered monocyclic heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur;which is optionally substituted; and R³ is an optionally substituted 5-6membered monocyclic heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur.
 14. The compound of claim 1,of formula I-h:

or a pharmaceutically acceptable salt thereof.
 15. The compound of claim14, wherein R¹ is —OR and R is C₁₋₆ aliphatic; and R² is 5-6 memberedmonocyclic heteroaryl ring having 1-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur; which is optionally substituted. 16.The compound of claim 1, selected from Table 1: TABLE 1

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

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58

59

60

61

62

63

64

65

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68

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71

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73

74

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79

80

81

82

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90

91

92

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96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

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148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

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171

172

173

174

175

176

177

178

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180

181

182

183

184

185

186

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190

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192

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195

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199

200

201

202

203

204

205

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207

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209

210

211

212

213

214

215

216

217

218


17. A pharmaceutical composition comprising a compound of claim 1, and apharmaceutically acceptable adjuvant, carrier, or vehicle.
 18. A methodfor treating a FSHR-mediated disorder in a patient in need thereof,comprising the step of administering to said patient a compound ofclaim
 1. 19. A method for treating fertility disorders in a subject,comprising the step of administering to said subject a compound of claim1 or a physiologically acceptable salt thereof.